Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis

Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJjNTRlNWI0MjExZWM3ZmY3MTRjNTBlZmExYmJhMmM2OCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4MzY2OTgwfQ.hREtsfZSpPN_jm_nlxQ8TJ1UyaLqkVI6Xc5WebL2-Iq33VX9say-45ADNlMjyM5weBXLHS9isrtvtCTOs7cd6iq2MNilwCZaEWdPK3C9kaxN_r63rR7XHlEfNeu-xAlo0YiIjqNT3GwGIlt4TIcUrseH0SXuNmRSGyueeDoGY53GZs5rVQyx9rPVwLyq2plJvSO7BIpyj24A5mFslFYflWP105QsY9ckJ42w7aT3XOly8XoeEeg66EPMQqk-hmu2J_gbzIIx_r6LX64gP6k89oy86YrxFCKPuF0qS4CIHUkP0C4tOo3ck57fb2yn0l07keAJWcDURrB_m2nXIbXANQ(mp4, (20.16 MB) Download video