title: Hydrogen sulfide induces the synthesis of proinflammatory cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway.
abstract: Hydrogen sulfide (H2S) is now considered an endogenous, gaseous mediator, which has been demonstrated to be involved in many inflammatory states. However, the mechanism of its proinflammatory function remains unknown. In the present study, we used IFN-gamma-primed human monocytic cell line U937 to investigate the effects of H2S in vitro on monocytes. We found that treatment with the H2S donor, sodium hydrosulfide, led to significant increases in the mRNA expression and protein production of TNF-alpha, IL-1beta, and IL-6 in U937 cells. H2S-triggered monocyte activation was confirmed further by the up-regulation of CD11b expression on the cell surface. We also observed that H2S could induce a rapid degradation of IkappaBalpha and subsequent activation of NF-kappaB p65, and this effect was attenuated by Bay 11-7082, a specific inhibitor of NF-kappaB. Furthermore, pretreatment of cells with Bay 11-7082 substantially inhibited the secretion of TNF-alpha, IL-1beta, and IL-6 induced by H2S. We also found that H2S stimulated the phosphorylation and activation of ERK1/2, but not of p38 MAPK and JNK, and pretreatment with PD98059, a selective MEK1 antagonist, could inhibit H2S-induced NF-kappaB activation markedly. Together, our findings suggest for the first time that H2S stimulates the activation of human monocytes with the generation of proinflammatory cytokines, and this response is, at least partially, through the ERK-NF-kappaB signaling pathway.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Life Sciences, 28 Medical Drive, Singapore 117456.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhi
authors.forename: Abel Damien
authors.initials: AD
authors.lastname: Ang
authors.forename: Huili
authors.initials: H
authors.lastname: Zhang
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D039481:CD11b Antigen / Q000096:biosynthesis / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000276:immunology; D005419:Flavonoids / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D039481:CD11b Antigen; D016207:Cytokines; D005419:Flavonoids; D020672:I-kappa B Proteins; C509295:ITGAM protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D012333:RNA, Messenger; D013440:Sulfides; D013450:Sulfones; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; C025451:sodium bisulfide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one