Interleukin-17 enhances the risk for tumor development in chronic sclerosing cholangitis

Background Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease, which leads to cirrhosis and increases the risk of hepatobiliary malignancy, e.g. hepatocellular carcinoma (HCC). PSC pathogenesis remains largely unknown, but patients bear increased numbers of IL-17A-producing CD4+ T cells. In this study we investigated the in vivo effect of IL-17 deficiency on inflammation, fibrosis and tumor development in a mouse model of sclerosing cholangitis.

Methods We analyzed B6-Mdr2-/- mice, an established mouse model of sclerosing cholangitis, crossed with IL-17 deficient animals at various time points (5, 36 and 66 weeks). Severity of liver fibrosis was determined by serum transaminases and quantification of Sirius red stained liver sections. Gene expression was analyzed by qPCR and flow cytometric analysis of hepatic and splenic lymphocytes was performed. Liver inflammation was quantified using the modified hepatic activity index (mHAI) score. Onset and growth of hepatic tumors was analyzed via small animal MRI scans. Western Blot analysis was performed to quantify Stat3 activation in liver tissue.

Results Deficiency in IL-17 significantly reduced liver fibrosis in mice analyzed at 5 weeks of age. In addition, collagen 1A1 levels were significantly decreased and flow cytometric analysis revealed reduced numbers of neutrophils within liver tissue of 5-week-old Mdr2-/- IL17-/-mice, compared to Mdr2-/- mice. Importantly, the observed difference vanished with age resulting in similar fibrosis levels in Mdr2-/- and Mdr2-/- IL-17-/- mice at the age of 36 and 66 weeks. Moreover, mHAI score, expression of collagen 1A1 and serum transaminases were not altered between the two analyzed groups at these time points. However, although the lack of IL-17 did not seem to affect fibrosis with age, we observed an increased HCC progression at the age of 66 weeks in Mdr2-/- IL-17 competent animals. HCC progression was associated with increased pStat3 levels, enhanced proliferation of hepatocytes and increased IL-6 levels in IL-17 competent Mdr2-/- animals.

Conclusion Several studies suggest tumor-promoting effects of IL-17 in the development, progression and recurrence of HCC in patients. We here demonstrate that IL-17 itself does not affect fibrosis development but significantly enhances the risk of developing HCC by activation of known pro-tumorigenic pathways. This work should stimulate further research on IL-17 in the setting of chronic inflammation.

Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021