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  • 201. Giha, Hayder A
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Ekström, Mattias
    Israelsson, Elisabeth
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Arambepola, Gishanthi
    Arnot, David
    Theander, Thor G
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Tornvall, Per
    ElGhazali, Gehad
    Association of a single nucleotide polymorphism in the C-reactive protein gene (-286) with susceptibility to Plasmodium falciparum malaria2010In: Molecular Medicine, ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 1-2, p. 27-33Article in journal (Refereed)
    Abstract [en]

    The role of inflammation in malaria pathogenesis is not fully understood, although C-reactive protein (CRP) may have a negative influence on host immunity to infections. An upstream polymorphism, -286 (C > T > A), in the CRP gene is known to influence CRP levels. In this study, a cohort of 192 Sudanese donors, followed for malaria infection for 9 years, had their CRP -286 gene locus genotyped by pyrosequencing. The number of malaria episodes experienced by each individual over the study period was used as an index for malaria susceptibility. The prevalence of the CRP alleles A, C and T were 21%, 52% and 27%, respectively. Importantly, the A-allele, unlike the C- and T-alleles or CRP genotypes, was significantly associated with an increased number of malaria episodes, P = 0.007. The proportion of A-allele carriers among donors not known to have had malaria during the study period was 18%, whereas it was 43% and 63% among donors who had experienced 1-4 and > or =5 malaria episodes, respectively, over the same period (P = 0.002). Furthermore, the A-allele was associated with higher parasite counts. In conclusion, the CRP -286 A-allele was associated with an increased susceptibility to uncomplicated Plasmodium falciparum malaria.

  • 202. Giha, Hayder A.
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Arnot, David
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Theander, Thor G.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Elghazali, Gehad
    Pandey, Janardan P.
    Antigen-specific influence of GM/KM allotypes on IgG isotypes and association of GM allotypes with susceptibility to Plasmodium falciparum malaria.2009In: Malaria Journal, E-ISSN 1475-2875, Vol. 8, no 1, article id 306Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: Plasmodium falciparum malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control. METHODS: In this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined. RESULTS: The GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent. DISCUSSION: The results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptible CONCLUSIONS: The GM allotypes have significant influence on susceptibility to uncomplicated P. falciparum malaria and antigen-dependent influence on total IgG and IgG subclasses.

  • 203. Giha, Hayder A.
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Balogun, Halima A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Arnot, David
    Theander, Thor G.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Elghazali, Gehad
    Age-dependent association between IgG2 and IgG3 subclasses to Pf332-C231 antigen and protection from malaria, and induction of protective antibodies by sub-patent malaria infections, in Daraweesh2010In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 7, p. 1732-1739Article in journal (Refereed)
    Abstract [en]

    The certainty of the protective role of acquired immunity in malaria is the major drive for malaria vaccine development. In this study, we measured the levels of total IgG and IgG subclasses to four candidate malaria vaccine antigens; MSP2-3D7, MSP2-FC27, AMA-1 and Pf332-C231, in plasma obtained from a cohort of 136 donors from Daraweesh in Sudan. The cohort was followed for malaria infection for 9 years. After an initial analysis, the immune response to Pf332-C231 antigen was the only one found associated with protection, thus taken for further analysis. The number of previous clinical malaria episodes experienced by the donors was used as an index for relative protection. The number of these episodes was found to be negatively correlated with the levels of pre-existing total IgG, IgG2 and IgG3 to Pf332-C231 (correlation coefficient, CC - 0.215, p=0.012; CC - 0.195, p=0.023 and CC - 0.211, p=0.014, respectively), and also with age (CC - 0.311, p<0.001). Unexpectedly, equal levels of Pf332-C231 antibodies were induced by both patent and sub-patent infections regardless of the number of previous malaria episodes (1-7). Combining the correlation analysis with a multi-linear regression, three variable markers for protection were emerged, two age-dependent, the antibody response to Pf332-C231 and an unidentified marker (likely immune response to other antigens), and the third was an age-independent unidentified marker (possibly gene polymorphisms). In conclusion, this report suggests a protective effect for IgG subclasses to Pf332-C231 antigen against malaria.

  • 204. Giha, Hayder A.
    et al.
    Nasr, Amre
    Iriemenam, Nnaemeka C.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    ElGhazali, Gehad
    Lack of significant influence for Fc gamma RIIa-RH131 or hemoglobin AA/AS polymorphisms on immunity and susceptibility to uncomplicated malaria and existence of marked linkage between the two polymorphisms in Daraweesh2012In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 14, no 6, p. 537-544Article in journal (Refereed)
    Abstract [en]

    Malaria signature on human genome is marked by several gene polymorphisms. HemoglobinAS (HbAS) is known to protect against severe malaria, but barely proved to protect against uncomplicated malaria (UM). Similarly, the influence of Fc gamma RIIa-RH131 polymorphism on malaria is controversial. Polymorphisms in both genes were examined and levels of IgG subclasses against four malaria antigens were measured for 250 Fulani's from Daraweesh, eastern Sudan. Morbidity data for up to nine years was available for 214 donors. Number of malaria episodes experienced by each individual during the study period was used as indicator for susceptibility to UM. PCR and RFLP were used for donors DNA genotyping and ELISA for antibodies measurement. Results revealed that neither Fc gamma RIIa-RH131 alleles/genotypes nor HbAA/AS was significantly associated with malaria morbidity or with levels of IgG to test antigens. Both polymorphisms were in Hardy-Weinberg Equilibrium, interestingly, there was strong association between the two polymorphisms (linkage disequilibrium - LD) with D' = 0.89. The association between the two polymorphisms was confirmed by analysis of independent material from a neighboring village. In conclusion, in Daraweesh both Fc gamma RIIa-RH131 and HbAA/AS genotypes, independently or together, were not major markers for UM susceptibility, however, marked LD was observed between the two polymorphisms.

  • 205. Giha, Hayder A.
    et al.
    Nasr, Amre
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Pandey, Janardan P.
    Elghazali, Gehad
    Associations of multi-locus polymorphisms in an immune network with susceptibility to uncomplicated Plasmodium falciparum malaria in Daraweesh village, Eastern Sudan2011In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, no 7, p. 1674-1681Article in journal (Refereed)
    Abstract [en]

    Susceptibility to uncomplicated malaria (UM), as to other forms of the disease, is genetically determined. Over 9-years of clinical and parasitological follow up of inhabitants of Daraweesh, in Eastern Sudan, the relative susceptibility to UM was estimated in terms of number of episodes experienced by each individual. Previously, we reported that the levels of IgG2 and IgG3 to Pf332-C231 malaria antigen are negatively correlated with number of malaria episodes. In addition, four molecular markers for malaria susceptibility (CRP -286, GM/KM haplotypes, FcγRIIa131 and HbAS) were tested. In this study, the above data were combined and reanalysed. The CRP -286A allele and GM 1,17 5,13,14,6 phenotype were previously found to be associated with increased susceptibility to malaria; however, individuals have both polymorphism together were not more susceptible to UM than the non-carriers of the same double polymorphism. The FcγRIIa-RR131 and HbAA genotypes taken individually or as double polymorphism were not associated with malaria susceptibility; however, their combination with any or both of the former polymorphisms was mostly associated with increased susceptibility to malaria. None of the four markers were associated with the levels of IgG2 and IgG3 against Pf332-C231. In conclusion, while our data support the polygenic nature of susceptibility to UM and highlighted the role of immune markers polymorphisms, the combinations of these markers were not predictable, i.e. the combination of the susceptibility markers will not necessarily render the carriers more susceptible to UM.

  • 206.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Characterization of antigen-presenting cell function in vitro and ex vivo2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Long-term protective immunity depends on proper initiation of professional antigen-presenting cells (APCs). Autoimmune disorders and certain infections can cause disease through modulation of APCs and thereby affecting the outcome of these diseases. This work aimed to investigate the behaviour of different APC subsets during conditions known to cause improper immune responses.

    In Paper I, the effects of an anti-inflammatory compound called Rabeximod, intended for treatment of rheumatoid arthritis were investigated on different subsets of APCs. The results showed that Rabeximod affected the differentiation and behaviour of inflammatory subsets of dendritic cells (DCs) and macrophages while no effects were observed on anti-inflammatory subsets. Our findings suggest that Rabeximod acts by inhibiting the functionality of inflammatory subsets of APCs.

    In Paper II, the effects of different malaria derived stimuli such as hemozoin (Hz) and infected red-blood cells (iRBCs) on monocyte-derived dendritic cells (MoDCs) were investigated. Both stimuli triggered activation and migration of MoDCs. MoDCs exposed to iRBCs induced allogeneic T-cell proliferation while those exposed to Hz did not. These results indicate that different malaria derived stimuli may differently affect DCs and that this could lead to improper and inefficient T-cell activation.

    In Paper III, innate aspects of malarial immunity were compared in children from two sympatric ethnic groups. We observed decreased activation of APCs and severely supressed TLR responses in Dogon children as compared to Fulani. This may indicate an important role for TLR and APC activation in the Fulani, known to be better protected against malaria than the Dogon.

    In summary, detailed knowledge of APC activation will be helpful in the understanding of specific effector immune responses. This could in turn, improve treatment of inflammatory disorders as well as the generation of efficient vaccines against infectious diseases.

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  • 207.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Dendritic cells and Plasmodium falciparum: studies in vitro and in the human host2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria is one of the world’s most threatening diseases. About half the world’s population is at risk of infection and the infection claims a million lives each year. A vast majority of the deaths occur in children below the age of 5 in sub-Saharan Africa. Survivors typically acquire immunity only after long time of repeated exposure and immunity is rapidly lost. Immunity is created by the activation of naive T cells and their differentiation into effector cells. The most potent activators of naive T cells are dendritic cells (DCs). The life cycle of DCs is adapted to find and process microbes in order to be able to present their antigens to T cells and thereby activate them. Antigen presentation typically takes place in the lymph nodes and that is why migration to these areas is an essential part of the DC life cycle. Various studies have shown that DC function may be hampered by the malaria parasite or its components.

    We have investigated activation and migratory capacities of DCs upon in vitro exposure of the malarial pigment hemozoin and Plasmodium falciparum infected red blood cells. Furthermore, we have assessed the activation status of blood DCs in the Fulani, a traditionally nomadic population that respond better to malaria infection and exhibit less clinical symptoms than other ethnicities living under similar conditions, and a neighbouring ethnic group, the Dogon, in Mali.

    Our results indicate that DCs are semi-activated upon malaria exposure in vitro, including enhanced migratory capacity, partial up-regulation of co-stimulatory markers and no IL-12, which may lead to inappropriate T-cell priming. We also observed that DCs from the Fulani have a higher degree of activation than DCs from the Dogon upon malaria exposure in vivo.

    We hypothesize that this increased DC activation may be the reason for the relatively increased protection against malaria.

    Taken together, our findings suggest that improper DC activation may contribute to poor immunity in Malaria.

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  • 208.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    The novel anti-rheumatic compound Rabeximod impairs differentiation and function of human pro-inflammatory dendritic cells and macrophages2011In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 216, no 1-2, p. 243-250Article in journal (Refereed)
    Abstract [en]

    Rabeximod (9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b]quinoxaline) is a synthetic compound that is currently being developed for the treatment of rheumatoid arthritis (RA). Here, we investigated the effects of Rabeximod on the functionality of human antigen-presenting cells (APCs) of myeloid origin. Different subsets of professional APCs were generated from human monocytes in vitro and simultaneously treated with different doses of Rabeximod. Although Rabeximod had no effect on the differentiation of monocytes into anti-inflammatory macrophages (AI-Ms), this compound impaired monocyte differentiation into monocyte-derived dendritic cells (MDCs) and pro-inflammatory allostimulated macrophages (Allo-Ms). MDCs that were treated with Rabeximod resulted in a significant decrease in their ability to pinocytose antigens, while no effect was exerted by the drug on the ability of Allo-Ms and AI-Ms to phagocytose. Furthermore, we observed a significant reduction in the allostimulatory ability of MDCs and Allo-Ms after treatment with Rabeximod, although this compound did not affect the low immunostimulatory capacity of AI-Ms. Conversely, the effect of Rabeximod in influencing cytokine secretion by APCs appeared to be limited. In conclusion, Rabeximod impairs differentiation of monocytes into different pro-inflammatory APCs, leading to impaired immunostimulatory abilities of these cells. Our observations shed light on the cellular mode of action and the immunomodulatory effect of Rabeximod.

  • 209.
    Giusti, Pablo
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Plasmodium falciparum-Infected Erythrocytes and beta-Hematin Induce Partial Maturation of Human Dendritic Cells and Increase Their Migratory Ability in Response to Lymphoid Chemokines2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 7, p. 2727-2736Article in journal (Refereed)
    Abstract [en]

    Acute and chronic Plasmodium falciparum infections alter theimmune competence of the host possibly through changes in dendriticcell (DC) functionality. DCs are the most potent activatorsof T cells, and migration is integral to their function. MatureDCs express lymphoid chemokine receptors (CCRs), expressionof which enables them to migrate to the lymph nodes, where theyencounter naïve T cells. The present study aimed to investigatethe impact of the synthetic analog to malaria parasite pigmenthemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs)on the activation status of human monocyte-derived DCs and ontheir expression of CCRs. Human monocyte-derived DCs partiallymatured upon incubation with β-hematin as indicated byan increased expression of CD80 and CD83. Both β-hematinand iRBCs provoked the release of proinflammatory and anti-inflammatorycytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosisfactor alpha, but not IL-12, and induced upregulation of thelymphoid chemokine receptor CXCR4, which was coupled to an increasedmigration to lymphoid ligands. Taken together, these resultssuggest that the partial and transient maturation of human myeloidDCs upon stimulation with malaria parasite-derived productsand the increased IL-10 but lack of IL-12 secretion may leadto suboptimal activation of T cells. This may in turn lead toimpaired adaptive immune responses and therefore insufficientclearance of the parasites.

  • 210.
    Giusti, Pablo
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Urban, Britta C
    Frascaroli, Giada
    Albrecht, Letusa
    Tinti, Anna
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Plasmodium falciparum-infected erythrocytes and beta-hematin induce partial maturation of human dendritic cells and increase their migratory ability in response to lymphoid chemokines.2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 7, p. 2727-2736Article in journal (Refereed)
    Abstract [en]

    Acute and chronic Plasmodium falciparum infections alter the immune competence of the host possibly through changes in dendritic cell (DC) functionality. DCs are the most potent activators of T cells, and migration is integral to their function. Mature DCs express lymphoid chemokine receptors (CCRs), expression of which enables them to migrate to the lymph nodes, where they encounter naïve T cells. The present study aimed to investigate the impact of the synthetic analog to malaria parasite pigment hemozoin, i.e., β-hematin, or infected erythrocytes (iRBCs) on the activation status of human monocyte-derived DCs and on their expression of CCRs. Human monocyte-derived DCs partially matured upon incubation with β-hematin as indicated by an increased expression of CD80 and CD83. Both β-hematin and iRBCs provoked the release of proinflammatory and anti-inflammatory cytokines, such as interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha, but not IL-12, and induced upregulation of the lymphoid chemokine receptor CXCR4, which was coupled to an increased migration to lymphoid ligands. Taken together, these results suggest that the partial and transient maturation of human myeloid DCs upon stimulation with malaria parasite-derived products and the increased IL-10 but lack of IL-12 secretion may lead to suboptimal activation of T cells. This may in turn lead to impaired adaptive immune responses and therefore insufficient clearance of the parasites.

  • 211.
    Golozoubova, Valeria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Cold-induced nonshivering thermogenesis: tissue origin, activation, recruitment2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Two types of heat production, shivering and nonshivering thermogenesis, are activated in mammals in the cold. In small mammals, nonshivering thermogenesis becomes the main source of heat upon long-term cold exposure. Cold-induced nonshivering thermogenesis is adrenergically mediated, and the accepted measure of the development of this type of thermogenesis is the thermogenic response of the animal placed in a thermoneutral environment to the injection or infusion of norepinephrine. Brown adipose tissue is regarded as the main source of cold-induced, adrenergically-mediated nonshivering thermogenesis. However, other tissues (e.g. muscle or liver) have also been suggested to contribute to the process. Heat produced in brown adipose tissue is the result of the functioning of a specific protein, uncoupling protein-1 (UCP1). Several proteins structurally related to UCP1 (UCP2, UCP3 and others) have been described. The tissue distribution of the expression of these proteins is broader than that of UCP1 (found only in brown adipocytes), and one of the potential functions ascribed to these proteins was mediation of nonshivering thermogenesis in tissues and organs different from brown adipose tissue.

    In the present thesis, the sites and mechanisms of nonshivering thermogenesis are discussed. Using UCP1-ablated mice as a model system, we have shown that UCP1-dependent, brown adipose tissue-derived nonshivering thermogenesis is the one and only type of nonshivering thermogenesis induced in the cold. No substitution of a thermogenic process by UCP2, UCP3 or any other protein occurs in the cold-acclimated UCP1-ablated mice.

    The thermogenic response to injected norepinephrine was shown here to consist of two components: a pharmacological (non-inducible by cold-acclimation) and a physiological (developing as a result of cold exposure) component, and this response therefore cannot, per se, be used as a measure of available adaptive nonshivering thermogenesis. It is, however, a relevant measure of cold-inducible nonshivering thermogenesis, if the comparison is made between warm- and cold-acclimated animals.

    The processes leading to an increase of the thermogenic capacity of brown adipose tissue (recruitment) are discussed, and the mechanisms behind the acute thermogenic response to several substances (benidipine, carteolol and arotinolol in particular) are analysed.

    An attempt is also made to clarify the mechanisms underlying the cold intolerance observed in hypothyroidism, an effect possibly dependent on inadequate function of brown adipose tissue and UCP1 expression. Absence of nuclear thyroid hormone receptors also resulted in cold intolerance, but the reason for this was not a lack of UCP1 expression or function, but rather the inability to activate this function. Our results provide new insights into the regulation of UCP1 expression by thyroid hormones and into the reasons for the development of cold sensitivity in the hypothyroid state.

  • 212. González-Fernández, Africa
    et al.
    Faro, Jose
    Fernández, Carmen
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immune responses to polysaccharides: lessons from humans and mice.2008In: Vaccine, ISSN 0264-410X, Vol. 26, no 3, p. 292-300Article in journal (Refereed)
  • 213. Gothefors, Leif
    et al.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Persson,, Lars Åke
    The Relevance and Future Role of the International Vaccine Institute (IVI)2007Report (Other academic)
  • 214. Grantham, Julie
    et al.
    Lassing, Ingrid
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Cell Biology.
    Controlling the cortical actin motor2012In: Protoplasma, ISSN 0033-183X, E-ISSN 1615-6102, Vol. 249, no 4, p. 1001-1015Article, review/survey (Refereed)
    Abstract [en]

    Actin is the essential force-generating component of the microfilament system, which powers numerous motile processes in eukaryotic cells and undergoes dynamic remodeling in response to different internal and external signaling. The ability of actin to polymerize into asymmetric filaments is the inherent property behind the site-directed force-generating capacity that operates during various intracellular movements and in surface protrusions. Not surprisingly, a broad variety of signaling pathways and components are involved in controlling and coordinating the activities of the actin microfilament system in a myriad of different interactions. The characterization of these processes has stimulated cell biologists for decades and has, as a consequence, resulted in a huge body of data. The purpose here is to present a cellular perspective on recent advances in our understanding of the microfilament system with respect to actin polymerization, filament structure and specific folding requirements.

  • 215.
    Greicius, Gediminas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Links between activation and cytoskeletal regulation of B lymphocytes2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Interplay between adhesion molecules and the cytoskeleton is involved in many aspects of B lymphocyte behaviour during an immune response. Events such as cell polarisation and locomotion, collaboration with T lymphocytes and segregation in secondary lymphoid tissues all include mechanisms that recognise microenvironment and accordingly adjust morphological features of the cell. Their role in the functions of the immune system is strengthened by devastating effects observed in the absence of adhesion molecules involved in lymphocyte extravasation or in a disease known as Wiskott-Aldrich syndrome. The latter deficiency is associated with mutations in Wiskott-Aldrich syndrome protein (WASP) that among other features manifest in a decreased villosity of leukocyte membranes, presumably due to abnormal actin polymerisation.

    The adhesive capacity of B cells is regulated by a variety of soluble and immobilised factors. In this thesis we concentrated our attention on the role of IL-4 and cross-linking of CD40. These stimuli partially mimic signals received during B and T lymphocyte collaboration and are critical for B cell differentiation. We found that both these stimuli increased LFA-1 dependent adhesion of B lymphocytes. Additionally, the extent of cell aggregation was correlated with an increased cell locomotion, spreading and induction of microvilli-like extensions of the plasma membrane. This indicates that IL-4 or cross-linking of CD40 induced global changes in plasticity of cortical cytoskeleton. The molecular mechanisms behind these changes are not clear in detail. However, we demonstrate that the transcription factor STAT6 is needed for IL-4 induced changes in morphology of B cells. Also, changes in cortical cytoskeleton induced by CD40 and IL-4 are partially dependent on intact Cdc42/WASP system. Our findings suggest that IL-4 or CD40 signaling operate different molecular machinery in regulation of cell surface architecture and also indicate that B cells possess WASP-independent ways to regulate cortical cytoskeleton.

    Homotypic adhesion of activated B lymphocytes can involve adhesion systems other than the LFA-1. Carcinoembryonic antigen related cell-cell adhesion molecule-1 (CEACAM1, CD66a) belongs to the Ig superfamily and mediates homotypic cell-cell interactions. Hypothetically, aggregation of B lymphocytes would favour homophilic adhesion systems. Surprisingly, antibodies to CEACAM1 upregulated LFA-1 mediated binding. Also, cross-linking of CEACAM1 on the surface of B lymphocytes co-stimulates B cell receptor (BCR) induced proliferation and supports the initial steps of B cell differentiation.

    Overall, our results indicate that B lymphocytes possess several mechanisms that control cortical cytoskeleton and the architecture of the cell surface, modulating adhesive interactions with surrounding cells. These adhesive interactions may influence signaling via BCR and the initial steps of B cell differentiation and survival.

  • 216.
    Grenklo, Staffan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cross-linked Profilin:actin - A tool to study actin dynamics in non-muscle cells2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The microfilament system, consisting of actin and a number of auxiliary proteins, is fundamental for cell motility. Its dynamic organization depends on receptor-mediated signals, leading to rapid polymerizations and depolymerizations of actin. Profilin binds to non-filamentous actin, inhibits spontaneous filament formation, and functions as a regulator of actin polymerization. The profilin:actin complex, is thought to be the principal source of actin for filament formation although the role of profilin is not fully elucidated.

    In this thesis, a cross-linked profilin:actin complex (PxA), that retains the properties of ordinary profilin:actin, except for being non-dissociable, has been used to characterize the role of profilin and profilin:actin in non-muscle cells. A rapid screening method, employing PxA and based on the far western technique and mass-spectrometry, was designed to identify cellular components that specifically bind profilin:actin. Microinjection of PxA into cells infected with the bacteria Listeria monocytogenes impaired bacterial motility but a mutant PxA, unable to bind proline-rich sequences had no effect, demonstrating that profilin:actin is vital for the activity of the actin polymer-forming complex that the pathogen recruits to its surface upon infection.

    Fluorescence microscopy using two distinct sets of affinity-purified actin and profilin antibodies generated against PxA enabled localization of monomeric actin in cells. One of the actin and both profilin antibodies resulted in a dotted pattern of fluorescence partially aligning with microtubules whereas the other actin antibody detected filamentous actin. The result demonstrates extensive variability in epitope recognition, and indicates that unpolymerized actin, i.e. profilin:actin and maybe other complex-bound forms of actin, distributes in small packages that might be transported along microtubules. Microinjection of PxA into lamprey axons demonstrated the involvement of actin polymerization during synaptic signaling.

  • 217.
    Grenklo, Staffan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Geese, Marcus
    Department of Cell Biology, Gesellschaft für Biotechnologische Forschung (GBF).
    Lindberg, Uno
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Cell Biology.
    Wehland, Jürgen
    Department of Cell Biology, Gesellschaft für Biotechnologische Forschung (GBF).
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Department of Cell Biology.
    Sechi, Antonio S
    Department of Cell Biology, Gesellschaft für Biotechnologische Forschung (GBF).
    A crucial role for profilin-actin in the intracellular motility of Listeria monocytogenes2003In: EMBO reports, ISSN 1469-221, Vol. 4, no 5, p. 523-529Article in journal (Refereed)
    Abstract [en]

    We have examined the effect of covalently crosslinked profilin–actin (PxA), which closely matches the biochemical properties of ordinary profilin–actin and interferes with actin polymerization in vitro and in vivo, on Listeria monocytogenes motility. PxA caused a marked reduction in bacterial motility, which was accompanied by the detachment of bacterial tails. The effect of PxA was dependent on its binding to proline-rich sequences, as shown by the inability of PH133SxA, which cannot interact with such sequences, to impair Listeria motility. PxA did not alter the motility of a Listeria mutant that is unable to recruit Ena (Enabled)/VASP (vasodilator-stimulated phosphoprotein) proteins and profilin to its surface. Finally, PxA did not block the initiation of actin-tail formation, indicating that profilin–actin is only required for the elongation of actin filaments at the bacterial surface. Our findings provide further evidence that profilin–actin is important for actin-based processes, and show that it has a key function in Listeria motility.

  • 218. Grenklo, Staffan
    et al.
    Hillberg, Louise
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Zhao Rathje, Li-Sophie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Pinaev, George
    Schutt, Clarence E.
    Lindberg, Uno
    Tropomyosin assembly intermediates in the control of MF-system turnover2008In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 87, no 11, p. 905-920Article in journal (Refereed)
    Abstract [en]

    Tropomyosin is a coiled-coil α-helical protein, which self-associates in a head-to-tail fashion along polymers of actin to produce thin filaments. Mammalian non-muscle cells express a large number of tropomyosin isoforms, which are differentially regulated during embryogenesis and associated with specialized actin microfilament ensembles in cells. The function of tropomyosin in specifying form and localization of these subcellular structures, and the precise mechanism(s) by which they carry out their functions, is unclear. This paper reports that, while the major fraction of non-muscle cell tropomyosin resides in actin thin filaments of the cytomatrix, the soluble part of the cytoplasm contains tropomyosins in the form of actin-free multimers, which are isoform specific and of high molecular weight (MWapp 180,000–250,000). Stimulation of motile cells with growth factors induces a rapid, actin polymerization-dependent outgrowth of lamellipodia and filopodia. Concomitantly, the levels of tropomyosin isoform-specific multimers decrease, suggesting their involvement in actin thin filament formation. Malignant tumor cells have drastically altered levels and composition of tropomyosin isoform-specific multimers as well as tropomyosin in the cytomatrix.

  • 219.
    Grenklo, Staffan
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Johansson, Thomas
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Bertilsson, Louise
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Karlsson, Roger
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Anti-actin antibodies generated against profilin: actin distinguish between non-filamentous and filamentous actin, and label cultured cells in a dotted pattern2004In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 83, no 8, p. 413-423Article in journal (Refereed)
    Abstract [en]

    Actin polymerization is a prominent feature of migrating cells, where it powers the protrusion of the leading edge. Many studies have characterized the well-ordered and dynamic arrangement of filamentous actin in this submembraneous space. However, less is known about the organization of unpolymerized actin. Previously, we reported on the use of covalently coupled profilin:actin to study actin dynamics and presented evidence that profilin-bound actin is a major source of actin for filament growth. To locate profilin:actin in the cell we have now used this non-dissociable complex for antibody generation, and obtained monospecific anti-actin and antiprofilin antibodies from two separate immunizations. Fluorescence microscopy revealed drastic differences in the staining pattern generated by the anti-actin antibody preparations. With one, distinct puncta appeared at the actin-rich leading edge and sometimes aligned with microtubules in the interior of the lamella, while the other displayed typical actin filament staining. Labelling experiments in vitro demonstrated failure of the first antibody to recognize filamentous actin and none of the two bound microtubules. The two anti-profilin antibodies purified in parallel generated a punctated pattern similar to that seen with the first anti-actin antibody. All antibody preparations labelled the nuclei.

  • 220.
    Grenklo, Staffan
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Tomilin, Nikolay
    Evergren, Emma
    Brodin, Lennart
    Karlsson, Roger
    Shupliakov, Oleg
    Omega-shaped structures in the active zone caused by non-dissociable profilin:actinManuscript (Other academic)
  • 221. Gryseels, Bruno
    et al.
    Zumla, Alimuddin
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Kieny, Marie Paule
    Quaglio, Gianluca
    Holtel, Andreas
    Laang, Hannu
    Romaris, Manuel
    De Magistris, Maria Teresa
    Nuez, Ana Nieto
    Olesen, Ole F
    Ghalouci, Rachida
    Lönnroth, Anna
    European Union conference on poverty-related diseases research.2009In: The Lancet Infectious Diseases, ISSN 1474-4457, Vol. 9, no 6, p. 334-7Article in journal (Refereed)
  • 222. Guerra, Lina
    et al.
    Guidi, Riccardo
    Slot, Ilse
    Callegari, Simone
    Sompallae, Ramakrishna
    Pickett, Carol L.
    Åström, Stefan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Eisele, Frederik
    Wolf, Dieter
    Sjögren, Camilla
    Masucci, Maria G.
    Frisan, Teresa
    Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival2011In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 16, p. 2735-2742Article in journal (Refereed)
    Abstract [en]

    The DNA damage response triggered by bacterial cytolethal distending toxins (CDTs) is associated with activation of the actin-regulating protein RhoA and phosphorylation of the downstream-regulated mitogen-activated protein kinase (MAPK) p38, which promotes the survival of intoxicated (i.e. cells exposed to a bacterial toxin) cells. To identify the effectors of this CDT-induced survival response, we screened a library of 4492 Saccharomyces cerevisiae mutants that carry deletions in nonessential genes for reduced growth following inducible expression of CdtB. We identified 78 genes whose deletion confers hypersensitivity to toxin. Bioinformatics analysis revealed that DNA repair and endocytosis were the two most overrepresented signaling pathways. Among the human orthologs present in our data set, FEN1 and TSG101 regulate DNA repair and endocytosis, respectively, and also share common interacting partners with RhoA. We further demonstrate that FEN1, but not TSG101, regulates cell survival, MAPK p38 phosphorylation, RhoA activation and actin cytoskeleton reorganization in response to DNA damage. Our data reveal a previously unrecognized crosstalk between DNA damage and cytoskeleton dynamics in the regulation of cell survival, and might provide new insights on the role of chronic bacteria infection in carcinogenesis.

  • 223. Guillou, Hervé
    et al.
    Zadravec, Damir
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Martin, Pascal G P
    Jacobsson, Anders
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice2010In: Progress in lipid research, ISSN 0163-7827, E-ISSN 1873-2194, Vol. 49, no 2, p. 186-99Article in journal (Refereed)
    Abstract [en]

    In mammalian cells, elongases and desaturases play critical roles in regulating the length and degree of unsaturation of fatty acids and thereby their functions and metabolic fates. In the past decade, a great deal has been learnt about these enzymes and the first part of this review summarizes our current knowledge concerning these enzymes. More recently, several transgenic mouse models lacking either an elongase (Elovl3(-/-), Elovl4(-/-), Elovl5(-/-), Elovl6(-/-)) or a desaturase (Scd-1(-/-), Scd-2(-/-), Fads2(-/-)) have been developed and the second part of this review focuses on the insights gained from studies with these mice, as well as from investigations on cell cultures.

  • 224.
    Haecker, Achim
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Bergman, Mattias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Neupert, Christine
    Moussian, Bernard
    Luschnig, Stefan
    Aebi, Markus
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Wollknauel is required for embryo patterning and encodes the Drosophila ALG5 UDP-glucose:dolichyl-phosphate glucosyltransferase.2008In: Development, ISSN 0950-1991, Vol. 135, no 10, p. 1745-9Article in journal (Refereed)
  • 225. Haecker, Achim
    et al.
    Dai, Qi
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Lilja, Tobias
    Moussian, Bernard
    Andrioli, Luiz Paulo
    Luschnig, Stefan
    Mannervik, Mattias
    Drosophila Brakeless interacts with Atrophin and is required for Tailless-mediated transcriptional repression in early embryos2007In: Plos Biology, Vol. 5, p. 1298-1308Article in journal (Refereed)
  • 226.
    Haecker, Achim
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Qi, Dai
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Lilja, Tobias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Moussian, Bernard
    Andrioli, Luiz Paulo
    Luschnig, Stefan
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Drosophila brakeless interacts with atrophin and is required for tailless-mediated transcriptional repression in early embryos.2007In: PLoS Biol, ISSN 1545-7885, Vol. 5, no 6, p. e145-Article in journal (Refereed)
  • 227. Haecker, Achim
    et al.
    Qi, Dai
    Lilja, Tobias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Moussian, Bernard
    Andrioli, Luiz Paulo
    Luschnig, Stefan
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Drosophila Brakeless interacts with Atrophin and is required for Tailless-mediated transcriptional repression in early embryos2007In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 6Article in journal (Refereed)
    Abstract [en]

    Complex gene expression patterns in animal development are generated by the interplay of transcriptional activators and repressors at cis-regulatory DNA modules (CRMs). How repressors work is not well understood, but often involves interactions with co-repressors. We isolated mutations in the brakeless gene in a screen for maternal factors affecting segmentation of the Drosophila embryo. Brakeless, also known as Scribbler, or Master of thickveins, is a nuclear protein of unknown function. In brakeless embryos, we noted an expanded expression pattern of the Krüppel (Kr) and knirps (kni) genes. We found that Tailless-mediated repression of kni expression is impaired in brakeless mutants. Tailless and Brakeless bind each other in vitro and interact genetically. Brakeless is recruited to the Kr and kni CRMs, and represses transcription when tethered to DNA. This suggests that Brakeless is a novel co-repressor. Orphan nuclear receptors of the Tailless type also interact with Atrophin co-repressors. We show that both Drosophila and human Brakeless and Atrophin interact in vitro, and propose that they act together as a co-repressor complex in many developmental contexts. We discuss the possibility that human Brakeless homologs may influence the toxicity of polyglutamine-expanded Atrophin-1, which causes the human neurodegenerative disease dentatorubral-pallidoluysian atrophy (DRPLA).

  • 228.
    Hammarström, Sten
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Structure, specificity and binding properties of a blood group A reactive hemagglutinin from the snail Helix pomatia1972Doctoral thesis, comprehensive summary (Other academic)
  • 229.
    Hansson, Monika
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mercury-induced autoimmunity: Genetics and immunoregulation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

    In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

    We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait.

    We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

    Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

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  • 230.
    Hansson, Monika
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mercuric chloride induces a strong immune activation, but does not accelerate the development of dermal fibrosis in tight-skin 1 (Tsk 1) mice2004In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 59, no 5, p. 469-477Article in journal (Refereed)
    Abstract [en]

    In susceptible mice, mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of immunoglobulin (Ig) G1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. We have previously hypothesized that mercury confers more adverse immunological effects on those mouse strains, which are genetically prone to develop spontaneous autoimmune diseases than on normal strains. In this study, we tested our hypothesis in tight skin 1 (Tsk1/+) mice, a murine model for human scleroderma. As a support for our hypothesis, we observed that in Tsk1/+ mice, B cells were spontaneously hyperactive and that treatment with mercury induced a strong immune/autoimmune response in these mice, but not in their non-Tsk (+/+) littermates. This response was characterized by the formation of high numbers of splenic IgG1, IgG2b and IgG3 antibody-secreting cells, increased serum levels of IgE, production of IgG1 antibodies against single-stranded DNA (ssDNA), trinitrophenol (TNP) as well as thyroglobulin and the development of renal IgG1 deposits. Neither Tsk1/+ mice nor F1 hybrid crosses between this strain, and mercury susceptible B10.S (H-2s) were able to produce IgG1-ANolA in response to mercury. Moreover, mercury-induced immune activation in Tsk1/+ was not able to potentiate the progression of skin fibrosis in this strain. Thus, exposure to mercury accelerates the immune dysregulation, but not the development of skin fibrosis in Tsk1/+ mice.

  • 231.
    Hansson, Monika
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Abedi-Valugerdi, Manuchehr
    Xenobiotic metal-induced autoimmunity:mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice2003In: Clinical and Experimental Immunology, Vol. 131, no 3, p. 405-414Article in journal (Refereed)
  • 232.
    Hansson, Monika
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Djerbi, Mounira
    Rabbani, Hodjattallah
    Mellstedt, Håkan
    Hassan, Mustapha
    DePierre, Joseph
    Abedi-Valugerdi, Manuchehr
    Interactions between Th1-type of autoimmunity (induced by collagen) and Th2-type of autoimmunity (induced by mercuric chloride)Article in journal (Refereed)
  • 233.
    Hedengren, Marika
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Borge, Karin
    Umeå Centre for Molecular Pathogenesis, Umeå University.
    Hultmark, Dan
    Umeå Centre for Molecular Pathogenesis, Umeå University.
    Expression and evolution of the Drosophila attacin/diptericin gene family2000In: Biochemical and Biophysical Research Communications, ISSN 0006-291X, Vol. 279, no 2, p. 574-81Article in journal (Refereed)
    Abstract [en]

    We describe the genes for three new glycine-rich antimicrobial peptides in (support the proposal that these glycine-rich antimicrobial peptides evolved from a common ancestor and are probably also related to proline-rich peptides such as drosocin. Drosophila, two attacinsAttC and AttD) and one diptericin (DptB). Their structuresAttC is similar to the nearby  AttA on a different chromosome. Intriguingly, and AttB genes. AttD is more divergent and locatedAttD  may encode an intracellular attacin tandem to the closely related DptB is linked inDiptericin. However, the  DptB and may be processed in an attacin-like fashion. All attacin and diptericin genes are induced after bacterial challenge. This induction is reduced in and unexpectedly also in gene product contains a furin-like cleavage siteimd mutants,Tl2 mutants. The 18w  mutation particularly affects the induction of AttC,  which may be a useful marker for 18w signaling.

  • 234.
    Hedengren, Marika
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Åsling, Bengt
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Dushay, Mitchell
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ando, Istvan
    Umeå Center for Molecular Pathogenesis, Umeå university.
    Ekengren, Sophia
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Wihlborg, Margareta
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hultmark, Dan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Relish, a central factor in the control of humoral but not cellular immunity in Drosophila1999In: Molecular cell, ISSN 1097-2765, Vol. 4, no 5, p. 827-37Article in journal (Refereed)
    Abstract [en]

    The NF-κB-like Relish gene is complex, with four transcripts that are all located within an intron of the Nmdmc gene. Using deletion mutants, we show that Relish is specifically required for the induction of the humoral immune response, including both antibacterial and antifungal peptides. As a result, the Relish mutants are very sensitive to infection. A single cell of E. cloacae is sufficient to kill a mutant fly, and the mutants show increased susceptibility to fungal infection. In contrast, the blood cell population, the hematopoietic organs, and the phagocytic, encapsulation, and melanization responses are normal. Our results illustrate the importance of the humoral response in Drosophila immunity and demonstrate that Relish plays a key role in this response.

  • 235.
    Hedengren Olcott, Marika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Relish and the Regulation of Antimicrobial Peptides in Drosophila melanogaster2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The fruit fly Drosophila melanogaster has been a powerful model system in which to study the immune response. When microorganisms breach the mechanical barrier of the insect, phagocytosing cells and a battery of induced antimicrobial molecules rapidly attack them. These antimicrobial peptides can reach micromolar concentrations within a few hours. This immediate response is reminiscent of the mammalian innate immune response and utilizes transcription factors of the NF-κB family.

    We have generated loss-of-function mutants of the NF-κB-like transcription factor Relish in order to investigate Relish's role in the Drosophila immune response to microbes. Relish mutant flies have a severely impaired immune response to Gram-negative (G-) bacteria and some Gram-positive (G+) bacteria and fungi and succumb to an otherwise harmless infection. The main reason for the high susceptibility to infection is that these mutant flies fail to induce the antimicrobial peptide genes. The cellular responses appear to be normal.

    Relish is retained in the cytoplasm in an inactive state. We designed a set of expression plasmids to investigate the requirements for activation of Relish in a hemocyte cell line after stimulation with bacterial lipopolysaccharide. Signal-induced phosphorylation of Relish followed by endoproteolytic processing at the caspase-like target motif in the linker region released the inhibitory ankyrin-repeat (ANK) domain from the DNA binding Rel homology domain (RHD). Separation from the ANK domain allowed the RHD to move into the nucleus and initiate transcription of target genes like those that encode the inducible antimicrobial peptides, likely by binding to κB-like sites in the promoter region.

    By studying the immune response of the Relish mutant flies in combination with mutants for another NF-κB-like protein, Dorsal-related immunity factor (Dif), we found that the Drosophila immune system can distinguish between various microbes and generate a differential response by activating the Toll/Dif and Imd/Relish pathways. The recognition of foreign microorganisms is believed to occur through pattern recognition receptors (PRRs) that have affinity for selective pathogen-associated molecular patterns (PAMPs). We found that the Drosophila PRRs can recognize G- bacteria as a group. Interestingly, the PRRs are specific enough to distinguish between peptidoglycans from G+ bacteria such as Micrococcus luteus and Bacillus megaterium and fungal PAMPs from Beauveria bassiana and Geotrichum candidum.

    This thesis also investigates the expression of the antimicrobial peptide genes, Diptericin B and Attacin C, and the putative intracellular antimicrobial peptide gene Attacin D, and explores a potential evolutionary link between them.

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  • 236.
    Hedengren-Olcott, Marika
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Olcott, Micael C
    Dept. of Microbiology, Oregon State University, Corvallis.
    Mooney, Duan T
    Ekengren, Sophia
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Geller, Bruce L
    Taylor, Barbara J
    Differential activation of the NF-kappaB-like factors Relish and Dif in Drosophila melanogaster by fungi and gram-positive bacteria2004In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, no 20, p. 21121-7Article in journal (Refereed)
    Abstract [en]

    The current model of immune activation in Drosophila melanogaster suggests that fungi and Gram-positive (G+) bacteria activate the Toll/Dif pathway and that Gram-negative (G-) bacteria activate the Imd/Relish pathway. To test this model, we examined the response of Relish and Dif (Dorsal-related immunity factor) mutants to challenge by various fungi and G+ and G- bacteria. In Relish mutants, the Cecropin A gene was induced by the G+ bacteria Micrococcus luteus and Staphylococcus aureus, but not by other G+ or G- bacteria. This Relish-independent Cecropin A induction was blocked in Dif/Relish double mutant flies. Induction of the Cecropin A1 gene by M. luteus required Relish, whereas induction of the Cecropin A2 gene required Dif. Intact peptidoglycan (PG) was necessary for this differential induction of Cecropin A. PG extracted from M. luteus induced Cecropin A in Relish mutants, whereas PGs from the G+ bacteria Bacillus megaterium and Bacillus subtilis did not, suggesting that the Drosophila immune system can distinguish PGs from various G+ bacteria. Various fungi stimulated antimicrobial peptides through at least two different pathways requiring Relish and/or Dif. Induction of Attacin A by Geotrichum candidum required Relish, whereas activation by Beauvaria bassiana required Dif, suggesting that the Drosophila immune system can distinguish between at least these two fungi. We conclude that the Drosophila immune system is more complex than the current model. We propose a new model to account for this immune system complexity, incorporating distinct pattern recognition receptors of the Drosophila immune system, which can distinguish between various fungi and G+ bacteria, thereby leading to selective induction of antimicrobial peptides via differential activation of Relish and Dif.

  • 237.
    Helmby, Helena
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Immune Regulation During Malaria Infection1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria is the largest parasitic disease in the world and is caused by the protozoon Plasmodium. The most severe form in humans is caused by Plasmodium falciparum. Immunity to malaria involves both cell-mediated and humoral responses and develops slowly over a period of ten to fifteen years, requiring repeated infections.

    This thesis describes work aimed at investigating some of the immunological mechanisms occurring during human and experimental murine infections. The results show that polyclonal and specific Immunoglobulin (Ig) E elevations occur during blood-stage P.falciparum and P.chabaudi infections and that it is the malaria parasite itself that is responsible for this IgE induction. Elevated levels of IgE in humans are correlated with severity of disease. Studies in mice showed that the genetic background and the number of infections influence the development of IgE antibodies.

    Interleukin (IL)-4 plays a major role in the switching of IgM/IgG to IgE antibody production and functions as a B cell stimulatory factor. Activated T cells are a major source for IL-4 in the immune response but recently other non-lymphocyte cell types, potent producers of IL-4, have been described. One such cell type is the FceRI+ non-B non-T (NBNT) cell, probably a cell of the basophilic lineage. The data presented in this thesis show that a population of IL-3-responsive IL-4-producing NBNT cells expand in the spleens of P.chabaudi infected mice during and shortly after peak parasitemia. During this time period the mice are anemic and display elevated levels of IL-3 in their serum. The expansion of IL-4 producing NBNT cells correlates with the switch from Th1 to Th2 that takes place in the spleen during this time period. Thus, NBNT cells may represent a source of IL-4 involved in directing the Th-response towards a Th2 phenotype.

    The changes in cellular dynamics that take place in the spleen and peripheral blood during a malaria infection are complex, and the kinetics apparently differ between spleen and peripheral blood. The changes in the spleen involve apoptosis during the peak parasitemia. Thus, apoptosis may be of importance in the control and development of the splenic immune response.

    Concomitant infections with the trematode worm Schistosoma mansoni and P.chabaudi malaria resulted in higher malaria parasitemia and increased mortality. The malaria specific Th1 response was not affected by the concomitant S.mansoni infection but a significant suppression of macrophage activity was seen. The malaria infection suppressed S.mansoni-specific antibody production and Th2 cytokine responses showing that both pathogens affected the immune response to the other infection. These data emphasize the importance for similar studies in humans since multiple infections are common in malaria endemic areas.

  • 238.
    Hemphälä, Johanna
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Genetic dissection of tubulogenesis in the Drosophila trachea2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The formation of branched tubular organs, such as the mammalian lung kidney and vascular system, is an essential process in animal development. The Drosophila tracheal (respiratory) system provides a genetic model system to study the highly ordered process of branch outgrowth and fusion required to form continuous tubular networks.

    In a transposon mutagenesis screen we identified several genes involved in the different steps of tracheal network formation, including branch fusion. We initially studied the differentiation of the fusion cell in the dorsal branches (DBs). The DBs consists of 5-6 cells, one of which acquires the fusion cell fate. Our results point to a role for Decapentaplegic (Dpp), the Drosophila homolog of transforming growth factor-b (TGFb), in inducing the DB fusion cells fate. The Delta/Notch pathway is then required to select and restrict the fusion cell fate to a single cell in the DBs.

    After the outgrowth and fusion of tracheal branches, the constituent tubes acquire distinct size and shapes to generate a functional tubular tissue. We have found that a mutation in the grainyhead (grh) gene cause the branches to elongate excessively. Cellular and ultrastructural analyses showed that this phenotype was generated by apical cell membrane overgrowth. It was further shown that the activity of Grh is modulated by Branchless, the key regulator of branch outgrowth. Mutations in the Na/K ATPase a subunit (ATP a) and the fasiclin II (fasII) genes, cause similar elongated tracheal tubes as the ones found in grh mutants, but instead these mutations affect the lateral subcellular compartment, independently of the function of Grh in the apical cell domain.

    In a search for downstream effectors of Grh, we found the krotzkopf verkehrt (kkv) gene, encoding a Drosophila chitin synthase. Analysis of kkv mutants suggests that a chitinous intralumenal cable, lacking in kkv embryos, is essential for the tracheal tubes to attain their correct length and diameter. The composition of the chitinous filament is also affected in mutants of various septate junction components, indicating that their tube size defects are at least in part caused by an inability to correctly assemble the intralumenal chitinous matrix formed by Kkv.

  • 239.
    Hemphälä, Johanna
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Uv, Anne
    Cantera, Rafael
    Bray, Sarah
    Samakovlis, Christos
    Grainy head controls apical membrane growth and tube elongation in response to Branchless/FGF signalling2003In: Development, ISSN 0950-1991, Vol. 130, no 2, p. 249-258Article in journal (Refereed)
  • 240. Hermsen, Cornelus C
    et al.
    Verhage, Danielle F
    Telgt, Denise S C
    Teelen, Karina
    Bousema, J Teun
    Roestenberg, Meta
    Bolad, Ahmed
    Berzins, Klavs
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Corradin, Giampietro
    Leroy, Odile
    Theisen, Michael
    Sauerwein, Robert W
    Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial.2007In: Vaccine, ISSN 0264-410X, Vol. 25, no 15, p. 2930-40Article in journal (Refereed)
  • 241.
    Herron, David
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Brown adipose tissue recruitment in-vivo and in-vitro1992Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Brown adipose tissue recruitment was studied in the newborn hamster and in brown adipocyte precursor cell cultures.

    In the newborn hamster, the development of the thermogenic potential of brown adipose tissue was followed by estimating the amount of the uncoupling protein thermogenin by the binding of GDP to the mitochondria. Between the ages of 12 and 20 days, GDP Binding to isolated mitochondria rose sharply, indicating a dramatic increase in the thermogenic potential of brown adipose tissue during this period. This increase in thermogenic potential correlated well with morphological observations on the development of the tissue. It was concluded that in the perinatal hamster, brown adipose tissue recruits at a relatively late stage and that the recruited tissue probably contributes to the attainment of homeothermy in this species. The mechanisms which regulate this recruitment remain largely unknown.

    Brown adipocyte precursor cells, isolated as part of a stromal-vascular fraction derived from the brown adipose tissue of rat and mouse, were grown in culture. Various aspects of the recruitment process in brown adipose tissue were studied with these cell culture systems. Chronically raising cyclic-AMP levels with cholera toxin accelerated the differentation of rat brown adipocyte precursor cells, measured as enhanced levels of cytochrome £-oxidase and lipoprotein lipase mRNAs, and decreased levels of actin mRNA. A 35 kDa protein, of unknown identity, was also induced by this treatment.

    The cellular recruitment of thermogenin was studied in differentiating mouse brown adipocyte precursor cells. Thermogenin was expressed at low levels, if at all, in untreated cultures. Short-term norepinephrine treatment dramatically increased thermogenin mRNA and protein levels in the differentiating cells. Induction by norepinephrine was maximal in the period around confluence. Pharmacological characterization suggested that the norepinephrine signal was transduced mainly through ß-receptors (ß3-subtype), but transduction through aj-receptors was also involved. The newly synthesized thermogenin was incorporated into the mitochondria. Degradation studies suggested the existence of two pools of thermogenin.

    Thus, brown adipose tissue recruitment was studied in-vivo and invitro. The in-vitro studies on brown adipocyte cell cultures substantiate a central role for norepinephrine in the regulation of the recruitment process.

  • 242.
    Hillberg, Louise
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Elements in regulation of the microfilament system2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with cell motility. The process of rapid actin polymerization in the lamellipodium of a migrating cell is responsible for its protrusion. Studies have been made on some of the elements behind this event and special interest has been focused on the protein tropomyosin. Muscle tropomyosin and its function in regulating muscle contraction, have been studied for decades, but there are also multiple tropomyosin isoforms in non-muscle cells, whose detailed function has not been revealed. Previous work at this department has shown an involvement of tropomyosin in the assembly of actin in vitro in the presence of gelsolin, and initial studies located tropomyosin to the lamellipodium of stimulated human fibroblasts. However, the general view is that tropomyosin is depleted from the advancing cell edge, observations noted in support of the current model of Arp2/3 dependent formation of actin filaments in lamellipodia. We have demonstrated the presence of tropomyosins in lamellae of migrating cells using different antibodies against non-muscle tropomyosin in indirect immunofluorescence. Also, the distribution of tagged non-muscle tropomyosin isoforms was analyzed in transfected cells. We conclude that tropomyosin is present in lamellipodia, all the way to their advancing edges. The presence of tropomyosin in the leading edge urges for tropomyosin to be taken into account when modelling cell motility. Furthermore, the nature of cytosolic tropomyosin was investigated by gel filtration chromatography and the conclusion was that in fibroblasts, approximately 10% of the tropomyosin is present in the cytosol, while the remaining 90% is associated with actin microfilaments in the cytomatrix. Interestingly, the soluble tropomyosin was found to exist mostly in a multimeric form of high molecular weight. Surprisingly, skeletal muscle tropomyosin and recombinant TM1 expressed in Escherichia coli forms multimers, a phenomenon not observed previously.

  • 243.
    Hillberg, Louise
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Zhao Rathje, Li-Sophie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nyåkern-Meazza, Maria
    Helfand, Brian
    Goldman, Robert D.
    Schutt, Clarence E.
    Lindberg, Uno
    Tropomyosins are present in lamellipodia of motile cells2006In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 85, no 5, p. 399-409Article in journal (Refereed)
    Abstract [en]

    This paper shows that high-molecular-weight tropomyosins (TMs), as well as shorter isoforms of this protein, are present in significant amounts in lamellipodia and filopodia of spreading normal and transformed cells. The presence of TM in these locales was ascertained by staining of cells with antibodies reacting with endogenous TMs and through the expression of hemaglutinin- and green fluorescent protein-tagged TM isoforms. The observations are contrary to recent reports suggesting the absence of TMs in regions,where polymerization of actin takes place, and indicate that the view of the role of TM in the formation of actin filaments needs to be significantly revised.

  • 244.
    Holmlund, U.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Amoudruz, P.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Johansson, M. A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Haileselassie, Y.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ongoiba, A.
    Kayentao, K.
    Traoré, B.
    Doumbo, S.
    Schollin, J.
    Doumbo, O.
    Montgomery, S. M.
    Sverremark-Ekström, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maternal country of origin, breast milk characteristics and potential influences on immunity in offspring2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 162, no 3, p. 500-509Article in journal (Refereed)
    Abstract [en]

    Breast milk contains pro- and anti-inflammatory cytokines and chemokines with potential to influence immunological maturation in the child. We have shown previously that country of birth is associated with the cytokine/chemokine profile of breast milk. In this study we have investigated how these differences in breast milk affect the cellular response of cord blood mononuclear cells (CBMCs) and intestinal epithelial cells (IECs, cell line HT-29) to microbial challenge. Ninety-five women were included: 30 from Mali in West Africa, 32 Swedish immigrants and 33 native Swedish women. CBMCs or IECs were stimulated in vitro with breast milk, alone or in combination with lipopolysaccharide (LPS) or peptidoglycan (PGN). Breast milk in general abrogated the LPS-induced down-regulation of surface CD14 and Toll-like receptor (TLR)-4 expression on CB monocytes, while inhibiting the PGN-induced TLR-2 up-regulation. However, breast milk from immigrant women together with LPS induced a lower CBMC release of interleukin (IL)-6 (P = 0·034) and CXCL-8/IL-8 (P = 0·037) compared with breast milk from Swedish women, while breast milk from Swedish women and Mali women tended to increase the response. The same pattern of CXCL-8/IL-8 release could be seen after stimulation of IECs (HT-29). The lower CBMC and IEC (HT-29) responses to microbial compounds by breast milk from immigrant women could be explained by the fact that breast milk from the immigrant group showed a divergent pro- and anti-inflammatory content for CXCL-8/IL-8, transforming growth factor-β1 and soluble CD14, compared to the other two groups of women. This may have implications for maturation of their children's immune responses.

  • 245. Holmlund, Ulrika
    et al.
    Wähämaa, Heidi
    Bachmayer, Nora
    Bremme, Katarina
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Palmblad, Karin
    The novel inflammatory cytokine high mobility group box protein 1 (HMGB1) is expressed by human term placenta.2007In: Immunology, ISSN 1365-2567, Vol. 122, no 3, p. 430-7Article in journal (Refereed)
  • 246.
    Holmqvist, Per-Henrik
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Boija, Ann
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Philip, Philge
    Crona, Filip
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Stenberg, Per
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Preferential Genome Targeting of the CBP Co-Activator by Rel and Smad Proteins in Early Drosophila melanogaster Embryos2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 6, article id e1002769Article in journal (Refereed)
    Abstract [en]

    CBP and the related p300 protein are widely used transcriptional co-activators in metazoans that interact with multiple transcription factors. Whether CBP/p300 occupies the genome equally with all factors or preferentially binds together with some factors is not known. We therefore compared Drosophila melanogaster CBP (nejire) ChIP-seq peaks with regions bound by 40 different transcription factors in early embryos, and we found high co-occupancy with the Rel-family protein Dorsal. Dorsal is required for CBP occupancy in the embryo, but only at regions where few other factors are present. CBP peaks in mutant embryos lacking nuclear Dorsal are best correlated with TGF-beta/Dpp-signaling and Smad-protein binding. Differences in CBP occupancy in mutant embryos reflect gene expression changes genome-wide, but CBP also occupies some non-expressed genes. The presence of CBP at silent genes does not result in histone acetylation. We find that Polycomb-repressed H3K27me3 chromatin does not preclude CBP binding, but restricts histone acetylation at CBP-bound genomic sites. We conclude that CBP occupancy in Drosophila embryos preferentially overlaps factors controlling dorsoventral patterning and that CBP binds silent genes without causing histone hyperacetylation.

  • 247.
    Holmqvist, Per-Henrik
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Genomic occupancy of the transcriptional co-activators p300 and CBP.2012In: Transcription, ISSN 2154-1272, Vol. 4, no 1, p. 18-23Article in journal (Refereed)
    Abstract [en]

    The p300 and CBP co-activators are histone acetylases and central regulators of transcription in metazoans. The genomic occupancy of p300/CBP detected by ChIP-seq experiments can be used to identify transcriptional enhancers. However, studies in Drosophila embryos suggest that there is a preference for some transcription factors in directing p300/CBP to the genome. Although p300/CBP occupancy in general correlates with gene activation, they can also be found at silent genomic regions, which does not result in histone acetylation. Polycomb-mediated H3K27me3 is associated with repression, but does not preclude p300/CBP binding. An antagonism between H3K27ac and H3K27me3 indicates that p300/CBP may be involved in switching between repressed and active chromatin states.

  • 248.
    Holmström, Therese E.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Fälting, Johanna M.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Differential signalling pathways for EGF versus PDGF activation of Erk1/2 MAP kinase and cell proliferation in brown pre-adipocytes2008In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 19, p. 3581-3592Article in journal (Refereed)
  • 249.
    Holmström, Therese E.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Mattsson, Charlotte L.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Wang, Yanling
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Iakovleva, Irina
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Non-transactivational, dual pathways for LPA-induced Erk1/2 activation in primary cultures of brown pre-adipocytes2010In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, no 16, p. 2664-75Article in journal (Refereed)
    Abstract [en]

    In many cell types, G-protein-coupled receptor (GPCR)-induced Erk1/2 MAP kinase activation is mediated via receptor tyrosine kinase (RTK) transactivation, in particular via the epidermal growth factor (EGF) receptor. Lysophosphatidic acid (LPA), acting via GPCRs, is a mitogen and MAP kinase activator in many systems, and LPA can regulate adipocyte proliferation. The mechanism by which LPA activates the Erk1/2 MAP kinase is generally accepted to be via EGF receptor transactivation. In primary cultures of brown pre-adipocytes, EGF can induce Erk1/2 activation, which is obligatory and determinant for EGF-induced proliferation of these cells. Therefore, we have here examined whether LPA, via EGF transactivation, can activate Erk1/2 in brown pre-adipocytes. We found that LPA could induce Erk1/2 activation. However, the LPA-induced Erk1/2 activation was independent of transactivation of EGF receptors (or PDGF receptors) in these cells (whereas in transformed HIB-1B brown adipocytes, the LPA-induced Erk1/2 activation indeed proceeded via EGF receptor transactivation). In the brown pre-adipocytes, LPA instead induced Erk1/2 activation via two distinct non-transactivational pathways, one G(i)-protein dependent, involving PKC and Src activation, the other, a PTX-insensitive pathway, involving PI3K (but not Akt) activation. Earlier studies showing LPA-induced Erk1/2 activation being fully dependent on RTK transactivation have all been performed in cell lines and transfected cells. The present study implies that in non-transformed systems, RTK transactivation may not be involved in the mediation of GPCR-induced Erk1/2 MAP kinase activation

  • 250. Holtel, Andreas
    et al.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Penas-Jimenez, Inmaculada
    EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development.2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 11-Article in journal (Refereed)
    Abstract [en]

    While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease-endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined--and well confined--area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria.

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