Lipopolysaccharide enhances TGFβ1 induction of PDGF‐B in bile duct epithelial cells: role of NF‐κB

Abstract

Platelet‐derived growth factor‐B (PDGF‐B) is a potent fibrogenic mediator in the liver. The PDGF‐BB homodimer is expressed by bile duct epithelial cells (BDECs) and contributes to liver fibrosis after bile duct ligation. The mechanism of PDGF‐B induction in BDECs is not known. Transforming growth factor β (TGFβ) and lipopolysaccharide (LPS) also contribute to the fibrogenic response after bile duct ligation. We tested the hypothesis that LPS enhances TGFβ1 induction of PDGF‐B in BDECs. Stimulation of MMNK‐1 cells or primary rat BDECs with LPS did not induce PDGF‐B mRNA expression, but LPS stimulation enhanced TGFβ1 induction of PDGF‐B mRNA. LPS did not affect TGFβ1 activation of a SMAD‐responsive luciferase construct. Rather, stimulation of MMNK‐1 cells with LPS, but not TGFβ1, caused IκBα degradation and activation of a NF‐κB‐responsive luciferase construct. Expression of an IκBα super‐repressor or dominant negative IKK2 inhibited activation of the NF‐κB‐responsive luciferase construct and attenuated the LPS potentiation of TGFβ‐induced PDGF‐B mRNA. The results indicate that LPS activation of a NF‐κB pathway enhances TGFβ1‐induced PDGF‐B expression in BDECs. Financial support: NIH R01 ES017537.