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The STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus-encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology. Vilnius University .
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2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 1, 165-174 p.Article in journal (Refereed) Published
Abstract [en]

In line with the B-lymphotropic nature of EBV, the virus is present in several types of B cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBNA-1 and LMPs (type II latency) in the classical Hodgkin lymphomas (cHL). We have previously reported that exposure of the in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and IL-4 induced the expression of LMP-1. Here we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. The induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer STAT6 and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma-derived lines and in tonsillar B cells infected with the EBNA-2-deficient EBV strain P3HR-1. Furthermore, co-culture of EBV-carrying BL cells with activated CD4(+) T cells resulted in the induction of LMP-1 in the absence of EBNA-2. As the Hodgkin/Reed-Sternberg are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in the EBV-positive cHLs.

Place, publisher, year, edition, pages
2011. Vol. 117, no 1, 165-174 p.
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-44312DOI: 10.1182/blood-2010-01-265272ISI: 000285963900026PubMedID: 20876453OAI: oai:DiVA.org:su-44312DiVA: diva2:360952
Note

authorCount :8

Available from: 2010-11-05 Created: 2010-11-05 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Activation, adhesion and motility of B lymphocytes in health and disease
Open this publication in new window or tab >>Activation, adhesion and motility of B lymphocytes in health and disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cells can be activated by T cell-dependent stimuli, such as CD40 ligation and cytokines, which induce extensive proliferation, class switch recombination and somatic hypermutation.

Epstein-Barr virus (EBV) can also induce B cell activation by mimicking T cell help through its main oncoprotein, latent membrane protein 1 (LMP-1). It is regulated by another EBV-encoded protein, EBV nuclear antigen 2 (EBNA-2), which is absent in Hodgkin and Burkitt lymphomas. We have studied LMP-1 induction by cytokines in vitro and shown that LMP-1 is induced through the transcription factor signal transducer and activator of transcription (STAT6) and a newly defined high-affinity STAT6-binding site.

When IL-4 is added together with lipopolysaccharide (LPS) or α-CD40 to B cells, it induces homotypic round and tight aggregates in vitro, whereas LPS alone does not induce such morphological changes. I describe here attempts to identify the molecules that regulate these responses.

I have shown that the Rho GTPase Cdc42 controls the spreading of B cells, whereas two other molecules in the same family, Rac1 and Rac2, control homotypic adhesion. Further, I have shown by conditional deletion of Cdc42 in B cells that it is important in the humoral immune response.  Dock10 is a guanosine nucleotide exchange factor (GEF) for Cdc42. It is expressed through all differentiation stages of B cell development. However, targeted deletion of Dock10 in B cells does not result in an aberrant phenotype. Furthermore, by studying conditional knockout mice for Dock10, Cdc42, Rac1 and Rac2, I have elucidated the mechanism of cytoskeletal changes during B cell activation, leading to adhesion and motility.

My results may lead to a better understanding of normal B cell activation and of EBV infection, which is associated with many human tumours and may help to understand cancer development and progression in B cells.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 64 p.
Keyword
B cells, activation, motility, IL-4, EBV, Dock10, Cdc42, Rac1 and Rac2
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-92944 (URN)978-91-7447-704-7 (ISBN)
Public defence
2013-10-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2013-09-12 Created: 2013-08-26 Last updated: 2013-09-09Bibliographically approved

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