title: Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation.
abstract: 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.
  
  
  
  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. (Hepatology 2017;65:2074-2089).
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Steinmetz
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Anubha
authors.initials: A
authors.lastname: Kashyap
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Zhivkova
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Alizor
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Ernst
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gottfried-Brand
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Janssen
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze-Bergkamen
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lotz
authors.affiliation: Department of Immunology, Department of Hematology and Van Creveld Clinic University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
authors.affiliation: Department of Hematology and Oncology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: General, Visceral and Transplant Surgery, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heise
authors.affiliation: General, Visceral and Transplant Surgery, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Lang
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.affiliation: I. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000187:drug effects* / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D053148:Caspase 3; C488368:Sirt1 protein, rat; D056564:Sirtuin 1