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Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation
Author(s) -
Steinmetz Caroline,
Kashyap Anubha,
Zhivkova Nataliya,
Alizor Henry,
Ernst Isabell,
GottfriedBrand Daniela,
Janssen Henning,
Teufel Andreas,
SchulzeBergkamen Henning,
Lotz Johannes,
Kuball Jürgen,
Theobald Matthias,
Heise Michael,
Lang Hauke,
Galle Peter R.,
Strand Dennis,
Strand Susanne
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29072
Subject(s) - human chorionic gonadotropin , immune system , inflammation , medicine , liver injury , immunology , endocrinology , gonadotropin , biology , hormone
Incidence and prevalence of inflammatory liver diseases has increased over the last years, but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune‐suppressive mechanisms of the human pregnancy hormone, chorionic gonadotropin (hCG), in the liver. hCG signaling activates silent mating type information regulation 2 homolog 1 (SIRT1), which deacetylates forkhead box o3 (FOXO3a), leading to repression of proapoptotic gene expression, because the immunosuppressive consequence attributed to the absence of caspase‐3 activity of hepatocellular interleukin 16 (IL‐16) is no longer processed and released. Thus, serum levels of IL‐16, a key chemotactic factor for CD4 + lymphocytes, were reduced and migration to injured hepatocytes prevented. Furthermore, elevated IL‐16 levels are found in the sera from patients with AIH, hepatitis B virus, hepatitis C virus, and nonalcoholic steatohepatitis. Conclusion : Here, we report that hCG regulates the SIRT1/FOXO3a axis in hepatocytes, resulting in immune suppression by attenuating caspase‐3–dependent IL‐16 processing and release, which concomitantly prevents autoaggressive T‐cell infiltration of the liver. Considering the low toxicity profile of hCG in humans, interrupting the inflammatory cycle by hCG opens new perspectives for therapeutic intervention of inflammatory liver diseases. (H epatology 2017;65:2074‐2089).