Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation

Abstract

Aims: 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 (H 2 S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H 2 S on inflammatory hepcidin induction. Results: H 2 S 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 H 2 S 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, H 2 S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H 2 S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine c-lyase (CSE), an endogenous H 2 S synthase, exaggerated inflammatory hepcidin expression in mice. Innovation: For the first time, we elucidated the effects and possible mechanisms of H 2 S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin. Conclusion: Our work demonstrates that H 2 S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation. Antioxid. Redox Signal. 24, 70-83.

Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

“…SIRT1 plays a significant role in the deacetylation of NF‐ƙB, which resulted in a decrease in proliferation proteins such as CyclinD1 and PCNA . Additionally, SIRT1 has been shown to downregulate STAT3 and reduced reactive astrogliosis . In this study, we observed a significant reduction in endogenous SIRT1 expression along with an increase in cell proliferation marker CyclinD1 after GMH.…”

“…Previous studies have demonstrated that SIRT1 plays an essential role in cell proliferation and cell survival . SIRT1 attenuates reactive astrogliosis by targeting nuclear factor ƙB (NF‐ƙB) and signal transducing activator of transcription 3 (STAT3) . Thus, IL‐17A activation of the IL‐17RA/C/EBPβ signaling pathway may play a role in reactive astrogliosis, whereas SIRT1 signaling pathways attenuate reactive astrogliosis after GMH.…”

Hepcidin regulation in the anemia of inflammation

“…The IL6 antibody Siltuximab lowered hepcidin and improved anemia in patients with multicentric Castleman’s Disease [52]. Hydrogen sulfide suppressed hepcidin and improved hypoferremia in LPS-treated mice by suppressing IL6 production and promoting sirtuin 1-mediated deacetylation of STAT3 to inhibit its activity [53]. …”

Atherosclerosis and the Hydrogen Sulfide Signaling Pathway – Therapeutic Approaches to Disease Prevention

“…For example, H 2 S upregulated SIRT1 to inhibit endoplasmic reticulum stress in PC12 cells [67] and to prevent H 2 O 2 -induced [68] or nicotinamide-induced [69] senescence in human umbilical vein endothelial cells (HUVECs). Besides HUVECs, previous studies from our group demonstrated that H 2 S increased SIRT1 expression to abolish the oxidative stress induced apoptosis in H9c2 cardiomyocytes [70] and previous studies from our group demonstrated [6] found that H 2 S attenuated inflammatory hepcidin partially by promoting SIRT1-mediated STAT3 deacetylation. SIRT3, one of the isoforms of SIRT family, has also been reported that it could be regulated by H 2 S to protect endothelial cells in an antioxidant manner [71].…”

“…CSE is generally located in cardiovascular system [5], liver [6], kidney [7] and gastrointestinal tract [8-10]. CBS protein expression is dominant in the brain [11], and its existence in other tissue has been confirmed (e.g., liver, kidney, uterus and gastrointestinal tract [12-14]).…”