IL-6-DEPENDENT STAT3 ACTIVATION AND INDUCTION OF PROINFLAMMATORY CYTOKINES IN PRIMARY SCLEROSING CHOLANGITIS.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6-dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. Methods: We recruited 50 PSC-patients (36 with inflammatory bowel disease (IBD), 14 without IBD), 12 patients with autoimmune hepatitis (AIH), and 36 healthy controls to measure cytokines in serum, bile, and immune cell supernatant using bead-based immunoassays as well as flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. Results: In PSC IL-6 specifically triggered phosphorylation of STAT3 in CD4+ T cells and lead to enhanced production of interferon (IFN)-gamma and interleukin (IL)-17A. Phospho-STAT3-positive CD4+ T cells correlated with systemic inflammation (CRP serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3-positive cells were enriched in the peribiliary liver stroma and represented CD4+ T cells with prominent production of IFN-gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN-gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. Conclusions: Our results demonstrate systemic and local activation of the IL-6/STAT3-pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.

PMID: 37256725