Epitope-specific engagement of the protein tyrosine phosphatase CD45 induces tumor necrosis factor-alpha gene expression via transcriptional mechanisms

Details

Serval ID
serval:BIB_5076BBFCF797
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Epitope-specific engagement of the protein tyrosine phosphatase CD45 induces tumor necrosis factor-alpha gene expression via transcriptional mechanisms
Journal
European Journal of Immunology
Author(s)
Estoppey  O., Sauty  A., Espel  E., Menoud  Z., Frei  P. C., Spertini  F.
ISSN
0014-2980 (Print)
Publication state
Published
Issued date
07/1996
Volume
26
Number
7
Pages
1475-80
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jul
Abstract
The common leukocyte antigen CD45 plays a central role in T cell activation in coupling the T cell receptor (TCR) to the phosphatidylinositol pathway via interactions with TCR-associated protein tyrosine kinases lck and fyn. We here demonstrate that engagement of CD45 by monoclonal antibodies (mAb) on activated T cells induces tumor necrosis factor (TNF)-alpha as well as TNF-beta, interleukin (IL)-2 and IL-3 gene expression. When human alloreactive T cells are stimulated with mAb 4B2, which recognizes a determinant common to all CD45 isoforms, a vigorous production of TNF-alpha mRNA was detected, which peaked 2 h later. Anti-CD45 mAb cross-linking was required. In contrast, neither mAb 10G10, which recognizes an epitope distinct from the one recognized by mAb 4B2, nor mAb UCHL-1, a CD45RO-specific antibody, induced any significant increase in TNF-alpha transcription. Nuclear run-on transcription assays demonstrated that CD45 cross-linking caused transcriptional activation of the TNF-alpha gene. De novo protein synthesis was not required, since incubation with cycloheximide (CHX) did not block transcriptional activation. CHX in contrast up-regulated TNF-alpha gene expression and increased transcript half-life, an effect that was under control of post-transcriptional mechanisms. Engagement of CD45 by itself did not affect transcript stability. CD45 ligation resulted in TNF-alpha secretion. These results indicate that in addition to its role in TCR/CD3-mediated T cell activation, CD45, in an epitope-specific manner, may act as a primary signaling molecule, leading to the transcriptional regulation and secretion of a major pro-inflammatory cytokine.
Keywords
Antibodies, Monoclonal/pharmacology Antigens, CD45/*immunology Epitopes/*immunology Gene Expression Regulation/drug effects/*immunology Humans Lymphocyte Activation Protein Synthesis Inhibitors/pharmacology Protein-Tyrosine-Phosphatase/*immunology RNA, Messenger/biosynthesis T-Lymphocytes/immunology/metabolism Transcription, Genetic/*immunology Tumor Necrosis Factor-alpha/drug effects/*genetics/secretion
Pubmed
Web of science
Create date
25/01/2008 15:19
Last modification date
20/08/2019 14:06
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