The hepatic stellate cell (HSC) is the predominant cell type responsible for 
excess collagen deposition during liver fibrosis. Both transforming growth 
factor-beta (TGF-beta), 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 
alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad 
signaling reduced alpha1(I) collagen mRNA expression in untreated or 
TGF-beta-treated HSCs, and when both signaling pathways were simultaneously 
inhibited, alpha1(I) collagen gene expression was essentially blocked. Both 
signaling pathways were found to independently and additively increase alpha1(I) 
collagen gene expression by transcriptional mechanisms. TGF-beta treatment 
increased alpha1(I) collagen mRNA half-life, mediated by increased stability of 
alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad 
signaling. In conclusion, both p38 MAPK and Smad signaling independently and 
additively regulate alpha1(I) collagen gene expression by transcriptional 
activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen 
mRNA stability.