TGF-β2 antagonizes IL-6-promoted cell survival
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Transforming growth factor beta is a key cytokine involved in the pathogenesis of fibrosis in many organs, whereas interleukin-6 plays an important role in the regulation of inflammation. They are both potent angiogenesis inducers with opposite effects on cell survival and apoptosis. TGF-β2 induces apoptosis; in contrast, IL-6 protects cells from apoptosis. The possible interaction between these two cytokines is indicated in various disease states. In this study, we have assessed the effect of TGF-β2 on IL-6 signaling and found that TGF-β2 could strongly inhibit IL-6-induced STAT3 activation and synergy with IL-6 resulting in enhanced SOCS3 expression. Interestingly, IL-6 also slows down the decay of TGF-β2 mRNA. Consistent with this mechanism, we found that TGF-β2 could antagonize IL-6 effect on cell survival in both γ-irradiation and UV light-induced apoptosis. Taken together, the finding shows that TGF-β2 serves as a negative regulator of IL-6 signaling and antagonizes the anti-apoptosis effect of IL-6.
KeywordsIL-6 TGF-β2 STAT3 Cell survival Apoptosis
This work was supported by Grant 31571439 from National Natural Science Foundation of China (J.Y.), Qingdao Scientific and Technological Innovation center for Marine Biomedicine Development Grant (2017-CXZX01-2-2), and startup funding of Ocean University of China (C.Z.).
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Conflicts of interest
The authors disclose no potential conflicts of interest.
- 3.Derynck R, Miyazono K (2008) The TGF-[beta] family. CSHL Press, New YorkGoogle Scholar
- 7.Namachivayam K, Blanco CL, MohanKumar K, Jagadeeswaran R, Vasquez M, McGill-Vargas L, Garzon SA, Jain SK, Gill RK, Freitag NE, Weitkamp JH, Seidner SR, Maheshwari A (2013) Smad7 inhibits autocrine expression of TGF-beta2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 304:G167–G180CrossRefGoogle Scholar
- 14.Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, Swamy SN, Ahn KS, Kumar AP, Tan BK, Hui KM, Sethi G (2013) Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta 1835:46–60PubMedGoogle Scholar
- 20.Litherland GJ, Elias MS, Hui W, Macdonald CD, Catterall JB, Barter MJ, Farren MJ, Jefferson M, Rowan AD (2010) Protein kinase C isoforms zeta and iota mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction. J Biol Chem 285:22414–22425CrossRefGoogle Scholar
- 21.Samsonov A, Zenser N, Zhang F, Zhang H, Fetter J, Malkov D (2013) Tagging of genomic STAT3 and STAT1 with fluorescent proteins and insertion of a luciferase reporter in the cyclin D1 gene provides a modified A549 cell line to screen for selective STAT3 inhibitors. PLoS ONE 8:e68391. https://doi.org/10.1371/journal.pone.0068391 CrossRefPubMedPubMedCentralGoogle Scholar