SMAD and p38 MAPK Signaling Pathways Independently Regulate α1(I) Collagen Gene Expression in Unstimulated and Transforming Growth Factor-β-stimulated Hepatic Stellate Cells

Abstract

The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-␤ (TGF-␤), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in ␣1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced ␣1(I) collagen mRNA expression in untreated or TGF-␤-treated HSCs, and when both signaling pathways were simultaneously inhibited, ␣1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase ␣1(I) collagen gene expression by transcriptional mechanisms. TGF-␤ treatment increased ␣1(I) collagen mRNA half-life, mediated by increased stability of ␣1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate ␣1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased ␣1(I) collagen mRNA stability.

Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

“…Other reports frequently instead demonstrated that such p38 activation peaks occurred at earlier time points, that is, 15 min to 2 h, depending on cell types. 43,44 Although we are unable to explain this discrepancy, it is possible that this difference could be explained by the finding that protein phosphatase-2A, which is potentially activated by TGF-b, might dephosphorylate activated p38 at early times. 45 However, we failed to examine whether the mechanism of p38 phosphorylation at the peak of 6 h was induced by the direct effect of binding TGF-b2 to the receptor or by secondary effects of other growth factors induced by TGF-b2.…”

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

“…Zinc inhibited both JNK phosphorylation and HSC migration. It has also been detected that the inhibiting of either p38 MAPK or Smad signaling reduces 1(I) collagen gene expression in untreated HSCs, and when both signaling pathways are simultaneously inhibited, 1(I) collagen gene expression is essentially blocked [63]. These data indicate that not only MAPK pathways but also TGF--induced signaling is important in the activation of HSCs.…”

S-Adenosylmethionine Blocks Collagen I Production by Preventing Transforming Growth Factor-β Induction of the COL1A2 Promoter

“…ERK, p38, phosphatidylinositol 3-kinase) (56), an increase in pERK1/2 and pp38 was observed in the presence of TGF␤. AdoMet pretreatment prevented the phosphorylation of ERK1/2 but not of p38.…”