title: Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation.
abstract: OBJECTIVE
  Anemia of inflammation is quite prevalent in hospitalized patients with poor prognosis. Concerns about the effectiveness and safety of iron supplementation have arisen, driving the demand for alternative therapies. Induction of hepatic hepcidin, the master hormone of iron homeostasis, causes anemia under inflammatory conditions. Previous studies indicated that hydrogen sulfide (H2S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H2S on inflammatory hepcidin induction.
  
  
  RESULTS
  H2S suppressed lipopolysaccharide (LPS)-induced hepcidin production and regulated iron homeostasis in mice by decreasing serum interleukin-6 (IL-6) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation; similar results were obtained in Huh7 cells exposed to conditioned medium from LPS-challenged THP-1 macrophages. Intriguingly, we found H2S also attenuated hepcidin levels in Huh7 cells and mouse primary hepatocytes in a sirtuin 1 (SIRT1)-dependent manner. By promoting SIRT1 expression and stabilizing SIRT1-STAT3 interactions, H2S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H2S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine γ-lyase (CSE), an endogenous H2S synthase, exaggerated inflammatory hepcidin expression in mice.
  
  
  METHODS
  For the first time, we elucidated the effects and possible mechanisms of H2S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin.
  
  
  CONCLUSIONS
  Our work demonstrates that H2S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation.
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Minjun
authors.initials: M
authors.lastname: Wang
authors.affiliation: 2 Department of Oncology, School of Medicine, Fudan University , Shanghai, China .
authors.forename: Wenbo
authors.initials: W
authors.lastname: Tang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Shen
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Weijun
authors.initials: W
authors.lastname: Wu
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Chengyi
authors.initials: C
authors.lastname: Li
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Xiling
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xin
authors.affiliation: 1 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai, China .|3 Department of Pharmacology, National University of Singapore , Singapore .
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D064451:Hepcidins; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D064451:Hepcidins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D056564:Sirtuin 1; D006862:Hydrogen Sulfide