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Lipopolysaccharide enhances transforming growth factor β1‐induced platelet‐derived growth factor‐B expression in bile duct epithelial cells
Author(s) -
Kassel Karen M,
Sullivan Bradley P,
Luyendyk James P
Publication year - 2012
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2011.06941.x
Subject(s) - transforming growth factor , platelet derived growth factor receptor , platelet derived growth factor , growth factor , smad , endocrinology , medicine , signal transduction , hepatic stellate cell , lipopolysaccharide , biology , microbiology and biotechnology , receptor
Background and Aim: Platelet‐derived growth factor (PDGF)‐B is a potent profibrogenic mediator expressed by bile duct epithelial cells (BDECs) that contributes to liver fibrosis after bile duct ligation. However, the mechanism of PDGF‐B induction in BDECs during cholestasis is not known. Transforming growth factor β (TGFβ) and lipopolysaccharide (LPS) also contribute to the profibrogenic response after bile duct ligation. We tested the hypothesis that LPS and TGFβ1 synergistically induce PDGF‐B expression in BDECs. Methods: Transformed human BDECs (MMNK‐1 cells) and primary rat BDECs were stimulated with LPS and/or TGFβ1, and signaling pathways through which LPS potentiates TGFβ1‐induced PDGF‐B mRNA expression were investigated. Results: Stimulation of MMNK‐1 cells with LPS alone did not significantly induce PDGF‐B mRNA expression. However, LPS co‐treatment enhanced TGFβ1 induction of PDGF‐B mRNA in MMNK‐1 cells and also in primary rat BDECs. Importantly, co‐treatment of MMNK‐1 cells with LPS and TGFβ1 also significantly increased PDGF‐BB protein expression. Interestingly, LPS did not affect TGFβ1 activation of a SMAD‐dependent reporter construct. Rather, stimulation of MMNK‐1 cells with LPS, but not TGFβ1, increased JNK1/2 phosphorylation. Expression of dominant negative JNK2, but not dominant negative JNK1, inhibited the LPS potentiation of TGFβ1‐induced PDGF‐B mRNA expression in MMNK‐1 cells. In addition, LPS treatment caused IκBα degradation and activation of a nuclear factor κB (NFκB)‐dependent reporter construct. Expression of an IκBα super repressor inhibited activation of NFκB and attenuated LPS potentiation of TGFβ1‐induced PDGF‐B mRNA. Conclusions: The results indicate that LPS activation of NFκB and JNK2 enhances TGFβ1‐induced PDGF‐B expression in BDECs.