Fibroblast Growth Factor 19 and Interleukin-8 in Primary Sclerosing Cholangitis New insights sprouting from the inflamed biliary tree

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease in which inflammation causes fibrotic strictures of the intra- and extrahepatic bile ducts. The bile ducts are thought to be initially damaged by the immune system, followed by a second hit through leakage of bile, containing toxic bile salts, to the surrounding liver tissue. We hypothesized that deficiency of the bile salt-homeostatic hormone Fibroblast Growth Factor 19 (FGF19) could contribute to this, but we found no decreased circulating FGF19 levels in PSC patients. Next, we discovered that human bile contains FGF19 in much higher concentrations than serum and that bile-exposed tissues such as bile ducts, gallbladder and small intestine have the receptors for FGF19 signaling. These findings suggest a signaling function of FGF19 in the biliary tract. Meanwhile, another group demonstrated anti-inflammatory effects of FGF19 (in a prostate cancer cell line). We therefore measured FGF19 and a large panel of cytokines in bile of PSC patients. We found that FGF19 concentrations in PSC bile are unaffected, but that from all cytokines determined, Interleukin-8 (IL8) was by far most abundantly present in bile of PSC patients. IL8 has pro-fibrotic and pro-proliferative effects in cultured human bile duct epithelial cells. In PSC, both fibrosis and malignancies of the biliary tract are important clinical and pathological hallmarks. The combined findings lead us to conclude that IL8, but not FGF19, may play a role in the pathogenesis of PSC. Targeting IL8-signaling in PSC may therefore have therapeutic potential.