Curcumin improves sclerosing cholangitis in Mdr2-/- mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation

Abstract

Background and Aim Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. Curcumin, the yellow pigment of the spice turmeric, has pleiotropic actions and attenuates hepatic damage in animal models of chemically-induced liver injury. Whether curcumin has beneficial effects in cholangiopathies is unknown. Methods Potential anti-cholestatic, anti-inflammatory and anti-fibrotic mechanisms of curcumin were explored in vivo in Mdr2−/− mice as a murine model of chronic cholangiopathy; as well as in vitro in a cholangiocyte cell line (HuCCT1) and portal myofibroblasts (MFBs) isolated from Mdr2−/− mice. Results Liver damage, cholestasis and fibrosis were reduced in Mdr2−/− mice after curcumin feeding. Moreover, curcumin inhibited cholangiocyte proliferation and expression of activation marker Vascular Cell Adhesion Molecule-1 (VCAM-1) in Mdr2−/− mice. Curcumin - similar to PPARγ synthetic agonist troglitazone - directly inhibited TNF-α induced inflammatory activation of cholangiocytes in vitro, whereas these beneficial effects of curcumin were largely blocked by a PPARγ synthetic antagonist. In addition, curcumin blocked proliferation and activation of portal MFBs by inhibiting ERK1/2 phosphorylation, thus contributing to reduced fibrogenesis. Conclusions These results show that curcumin may have multiple targets in liver including activation of PPARγ in cholangiocytes and inhibition of ERK1/2 signalling in MFBs, thereby modulating several central cellular events in a mouse model of cholangiopathy. Targeting these pathways may be a promising therapeutic approach to cholangiopathies.

Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis

“…We observed no difference in liver fibrosis in CCl 4 -injured WT or Msln -/-mice (at 1.5 months, Figure 1B). In concordance with this finding, the aPF markers MSLN and fibulin 2 were not upregulated in the livers of CCl 4 -injured mice target for anticancer therapy (25)(26)(27)(28)(29). In contrast to the embryonic mesothelium (30), MSLN is minimally expressed in adult humans and mice (20).…”

“…Here, we demonstrate that expression of MSLN is not restricted to tumorigenesis, but is strongly induced in aPFs in response to cholestatic liver injury ( Figure 1 and Supplemental Figure 1A). In support of this, Msln-KO mice developed a defect in the activation of cancer-associated myofibroblasts that resulted in reduced tumorigenesis (25)(26)(27)(28)(29). Despite extensive studies of human cancer cells, the functional properties of the MSLN/MUC16 signaling pathway remain poorly understood.…”

Role of Nuclear Receptors in the Biliary Epithelium

“…The latter observation has been linked to the ability of PPAR-γ activation to attenuate the effect of LPS on NF-ĸB signaling, suggesting a protective role against inflammation [21]. This assumption is further supported by the observation that activation of PPAR-γ by curcumin leads to a decreased expression of VCAM-1 on biliary epithelial cells of Mdr2 –/– mice [22]. When biliary epithelial cells are incubated with curcumin or other PPAR-γ agonists, they respond to TNF-α with a lesser expression of VCAM-1 [22].…”

Update on primary sclerosing cholangitis

“…Antifibrotic treatment strategies in preparation largely build on studies on the Abcb4 À/À mouse model. Some effects converge on nuclear receptor signaling pathways, including TGR5, FXR, and peroxisome proliferator activated receptor gamma (PPARc) [26,138]. So far, no nuclear receptor has been identified as a target of nor-UDCA [139].…”