TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes.
IL-12 is a macrophage-derived heterodimeric cytokine, capable of inducing proliferation, cytokine production, and cytotoxic activity of NK cells and T cells, and is critical for the development of Th1 responses. TGF-beta is an immunosuppressive cytokine that inhibits IL-12-mediated responses in NK and T cells. To determine the mechanism of action of TGF-beta, we examined its inhibitory effect on IL-12 signal-transduction pathway in T cells. Stimulation of activated T cells with IL-12 leads to tyrosine phosphorylation and activation of Jak-2 and Tyk-2 kinases and STAT3 and STAT4 transcription factors. Treatment of activated T cells with TGF-beta blocked IL-12-induced tyrosine phosphorylation and activation of both Jak-2 and Tyk-2 kinases. Furthermore, inhibition of Jak kinases by TGF-beta was associated with a decrease in tyrosine phosphorylation of STAT3 and STAT4 proteins. Abrogation of IL-12-induced Jak-Stat pathway by TGF-beta resulted in decreased T cell proliferation and IFN-gamma production, and increased apoptotic cell death. These findings highlight that TGF-beta inhibits IL-12-mediated responses by blocking IL-12 signal transduction in T cells.
Multiple Sclerosis Research Laboratory, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
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Bright
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Sriram
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053614:Janus Kinase 2; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D014443:Tyrosine; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse