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The 11th International Symposium on ALPD and Cirrhosis


Tatiana Kisseleva, MD, PhD

Dept.of Surgery, University of California, San Diego, La Jolla, CA

Alcoholic liver disease (ALD) progresses from a normal liver, to alcoholic steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Alcohol produces a systemic effect on other tissues and organs, including liver-brain axis and intestinal permeability. Liver is directly affected by alcohol. Alcohol-induced chronic hepatotoxicity results in systemic release of proinflammatory microbial products, toxic lipids (such as ceramides) and cytokines into the circulation, and exacerbates cytotoxic effect of alcohol on other organs, including development of insulin resistance and oxidative stress. Central nervous system (CNS) is the other major target of alcohol toxicity. Chronic alcohol consumption causes direct neurotoxic effects, such as neuronal apoptosis and astrogliosis, neurocognitive impairment. In addition, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier. Despite of intensive studies, the pathogenesis of alcohol-induced damage of the liver-brain axis is poorly understood. Furthermore, the role of Interleukine 17A (IL-17) cytokine in regulation of alcohol-mediated hepato- and neurotoxicity has not been evaluated. IL-17-producing T helper (Th17) cells originate from naïve Th0 cells via TGF-β1/IL-6/IL-23-dependent activation of retinoid-related orphan receptor γt (ROR γt), which plays the central role in Th17 proliferation and IL-17 production. IL-17 signaling was implicated in mediation of autoimmunity, psoriasis, rheumatoid arthritis, fibrosis and tumorigenesis. Here we demonstrate that genetic deletion of IL-17 signaling in mice devoid of IL-17 Receptor A (IL-17RA-/- mice) attenuates development of alcohol-induced progression steatohepatitis to fibrosis and HCC, and blocking IL-17 with anti-IL-17 antibody have a therapeutic effect on alcoholic liver fibrosis. In addition, administration of anti-IL-17 antibodies to mice with alcohol-induced liver fibrosis also prevented neuronal apoptosis and astrogliosis, suggesting that blocking of IL-17 may effectively prevent alcohol-induced hepato- and neurotoxicity. If proven, IL-17 may become an attractive target for anti fibrotic therapy of patients with alcohol-induced liver fibrosis and HCC.