Distinct mechanisms of inhibition of interleukin-6-induced Stat3 signaling by TGF-beta and alpha-thrombin in CCL39 cells.
We previously demonstrated that exposure of CCL39 lung fibroblast cells to alpha-thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription-3) protein via a mitogen-activated protein (MAP)-kinase dependent mechanism. In the present study, we investigated the mechanism of regulation of IL-6-induced signaling by transforming growth factor-beta (TGF-beta) and compared this to alpha-thrombin-mediated inhibition. We demonstrate that exposure of CCL39 cells to TGF-beta completely inhibits IL-6-induced Stat3 tyrosine phosphorylation and gp130 gene expression. However, in contrast to alpha-thrombin, TGF-beta-mediated inhibition did not require activation of the MAP kinase pathway. Also, unlike alpha-thrombin, TGF-beta-mediated inhibition requires synthesis of new proteins. Interestingly, TGF-beta and alpha-thrombin both inhibit IL-6-induced expression of gp130 mRNA levels. These results demonstrate that although the end effects are the same, alpha-thrombin and TGF-beta utilize distinct mechanisms to inhibit IL-6-induced Stat3 signaling.
Icogen Corporation, 454 North 34th Street, Seattle, Washington 98103, USA. gunajej@icogen.com
J J
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Gunaje
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GJ
Bhat
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011500:Protein Synthesis Inhibitors; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D003513:Cycloheximide; D013917:Thrombin