Elevated interleukin‐8 in bile of patients with primary sclerosing cholangitis

Abstract

Background & Aims To better understand the pathogenesis of primary sclerosing cholangitis, anti‐ and pro‐inflammatory factors were studied in bile. Methods Ductal bile of PSC patients (n = 36) and controls (n = 20) was collected by endoscopic retrograde cholangiography. Gallbladder bile was collected at liver transplantation. Bile samples were analysed for cytokines, FGF19 and biliary lipids. Hepatobiliary tissues of PSC and non‐PSC patients (n = 8–11 per patient group) were collected at transplantation and were analysed for IL8 and FGF19 mRNA expression and IL8 localization. The effect of IL8 on proliferation of primary human cholangiocytes and expression of pro‐fibrotic genes was studied. Results In PSC patients, median IL8 in ductal bile was 6.6 ng/ml vs. 0.24 ng/ml in controls. Median IL8 in gallbladder bile was 7.6 ng/ml in PSC vs. 2.2 and 0.3 ng/ml in two control groups. IL8 mRNA in PSC gallbladder was increased and bile ducts stained positive for IL8. In vitro, IL8 induced proliferation of primary human cholangiocytes and increased the expression of pro‐fibrotic genes. Conclusion Elevation of IL8 in bile of PSC patients, collected at different stages of disease, indicates an ongoing inflammatory stimulus that drives IL8 production. This challenges the idea that advanced PSC is a burned‐out disease, and calls for reconsideration of anti‐inflammatory therapy in PSC.

Bile‐Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile

“…It has been postulated that the presence of proinflammatory mediators in bile may reflect a continuous inflammatory insult on the cholangiocyte, leading to stimulation of fibrosis. (23,24) In accordance with this hypothesis, levels of IL-8 were also significantly elevated in the bile of PSC patients in this study compared to non-PSC controls (Supporting Fig. S5).…”

Methylation signatures in peripheral blood are associated with marked age acceleration and disease progression in patients with primary sclerosing cholangitis

“…Thus, a link between cholangiocyte senescence, an inflammation-associated secretory phenotype, and elevated IL-8 levels associated with clinical decompensation are consistent with an overall global picture of organ dysfunction in PSC. 34,35 Our data showing significant associations between age acceleration with serum ALP and GGT, as well as a trend to increased serum bile acids in patients with high age acceleration, suggest a link between the severity of cholestasis and accelerated aging in PSC. Indeed, prior studies have observed direct effects of bile acids on DNA methylation.…”

Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis

“…Thus our work provides novel observation as no prior studies have analysed FGF19 expression in the intestinal tissue of patients with cholestatic diseases and prior data come mostly from animal models of cholestasis. FGF19 expression was recently reported in other tissues, including the human gallbladder and the common bile duct, with only minor expression observed in the ileum1718. However, indirect evidence for the harmful effects of the FXR-FGF19 axis interruption on the liver brings recent study on intestinal failure-associated liver disease (IFALD).…”