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Downregulation of interleukin-12 (IL-12) responsiveness in human T cells by transforming growth factor-beta: relationship with IL-12 signaling.

TitleDownregulation of interleukin-12 (IL-12) responsiveness in human T cells by transforming growth factor-beta: relationship with IL-12 signaling.
Publication TypeJournal Article
Year of Publication1999
AuthorsPardoux C, Ma X, Gobert S, Pellegrini S, Mayeux P, Gay F, Trinchieri G, Chouaib S
JournalBlood
Volume93
Issue5
Pagination1448-55
Date Published1999 Mar 01
ISSN0006-4971
KeywordsCells, Cultured, Down-Regulation, Humans, Interleukin-12, Lymphocyte Activation, Signal Transduction, T-Lymphocytes, Transforming Growth Factor beta
Abstract

Interleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-beta1 (TGF-beta) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was undertaken to further elucidate the biochemical basis of the functional interaction between these two cytokines and to define the site of TGF-beta action on the signaling pathway activated by IL-12. Our data indicate that TGF-beta induced an inhibition of interferon-gamma (IFN-gamma) production without affecting the IL-12Rbeta1 and IL-12Rbeta2 subunits mRNA expression by activated T cells. We further show that TGF-beta has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF-beta was found to significantly inhibit IL-12-induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indicated that TGF-beta induced a decrease in IL-12-induced STAT4 DNA binding activity in T lymphocytes. This study suggests that TGF-beta influences IL-12 responsiveness at least in part by inhibiting early signaling events essential to gene induction in IL-12-activated T cells.

Alternate JournalBlood
PubMed ID10029570

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