Antagonistic Effects of TNF-α on TGF-β Signaling Through Down-Regulation of TGF-β Receptor Type II in Human Dermal Fibroblasts

摘要: Transforming growth factor-beta stimulates the production of extracellular matrix, whereas TNF-alpha has antifibrotic activity. Understanding molecular mechanism underlying antagonistic activities against TGF-beta is critical in context tissue repair and maintenance homeostasis. In present study, we demonstrated a novel by which blocks TGF-beta-induced gene signaling pathways human dermal fibroblasts. We showed that prevents trans activation, such as alpha2(I) collagen or inhibitor metalloproteinases 1, pathways, Smad3, c-Jun N-terminal kinase, p38 mitogen-activated protein kinases, without inducing levels inhibitory Smad7 down-regulates expression type II receptor (TbetaRII) proteins, but not I (TbetaRI), However, neither TbetaRII mRNA nor promoter activity was decreased TNF-alpha. TNF-alpha-mediated decrease inhibited treatment fibroblasts with either selective I-kappaB-alpha phosphorylation, BAY 11-7082, kinase/extracellular signal-regulated kinase inhibitor, PD98059. Calpain (ALLN), protease inhibits down-regulation TbetaRII. found triggered TbetaRII, leading to desensitization toward TGF-beta. Furthermore, these events seemed cause dramatic 1 systemic sclerosis These results indicated impaired response cells regulating turnover