Curcumin improves sclerosing cholangitis in Mdr2−/− mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation
- Anna Baghdasaryan1,
- Thierry Claudel1,
- Astrid Kosters2,
- Judith Gumhold1,
- Dagmar Silbert1,
- Andrea Thüringer3,
- Katharina Leski1,
- Peter Fickert1,
- Saul J Karpen2,4,
- Michael Trauner1
- 1Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria
- 2Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children's Liver Center, Houston, Texas, USA
- 3Institute of Pathology, Medical University Graz, Graz, Austria
- 4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Correspondence to Professor Michael Trauner, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria;
Contributors AB: Performed the experiments, data collection, wrote the manuscript draft. MT and SJK: Conception, critical revision and correction of article, final approval of the article. PF, TC, AK: Critical revision of the article, experimental help. AF, JG, DS, KL: Data collection, technical support.
- Revised 13 October 2009
- Accepted 29 October 2009
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 anticholestatic, anti-inflammatory and antifibrotic 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 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.
A commentary on this article will appear in the May issue
Funding This work was supported by the Austrian Science Foundation, grant numbers P18613-B05, P19118, SFB 3008 (to MT), DK56239 from NIH/NIDDK (to SJK) and by the PhD Program of Medical University of Graz.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.