Abstract
Bile duct epithelial cells (BDECs) contribute to liver fibrosis by expressing αVβ6 integrin, a critical activator of latent transforming growth factor β (TGFβ). β6 integrin (Itgβ6) mRNA induction and αVβ6 integrin expression in BDECs are partially TGFβ-dependent. However, the signaling pathways required for TGFβ-dependent Itgβ6 mRNA induction in BDECs are not known. We tested the hypothesis that the p38 MAPK signaling pathway contributes to TGFβ1 induction of Itgβ6 mRNA by activating SMAD and AP-1 transcription factors. Pretreatment of transformed human BDECs (MMNK-1 cells) with the p38 MAPK inhibitor SB203580 inhibited TGFβ1 induction of Itgβ6 mRNA. SB203580 pretreatment also inhibited TGFβ1 activation of a SMAD-dependent reporter construct, and expression of dominant negative SMAD3 (SMAD3ΔC) significantly reduced TGFβ1-induced Itgβ6 mRNA induction. Expression of JunB mRNA, but not other AP-1 proteins, increased in TGFβ1-treated MMNK-1 cells, and induction of JunB was p38-dependent. Consistent with a requirement for JunB induction, cycloheximide pretreatment inhibited TGFβ1 induction of Itgβ6 mRNA. Expression of a dominant negative AP-1 mutant (TAM67) also inhibited TGFβ1 induction of Itgβ6 mRNA. Overall, the results suggest that p38 contributes to TGFβ1-induced Itgβ6 mRNA expression in MMNK-1 cells by regulating activation of both SMAD and AP-1 transcription factors. NIH R01 ES017537
Published Version
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