The effect of hydrogen sulfide donors on lipopolysaccharide-induced formation of inflammatory mediators in macrophages.
The role of hydrogen sulfide (H(2)S) in inflammation is controversial, with both pro- and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H(2)S, which give a rapid bolus of H(2)S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H(2)S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H(2)S donor (GYY4137) on the release of pro- and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1beta, IL-6, TNF-alpha, nitric oxide (*NO), and PGE(2) but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kappaB/ATF-2/HSP-27-dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1beta, IL-6, NO, PGE(2) and TNF-alpha. This study clearly shows that the effects of H(2)S on the inflammatory process are complex and dependent not only on H(2)S concentration but also on the rate of H(2)S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro- versus antiinflammatory role of H(2)S.
Whiteman
Matthew
M
Peninsula Medical School, University of Exeter, St. Luke's Campus, Exeter, Devon, England.
Li
Ling
L
Rose
Peter
P
Tan
Choon-Hong
CH
Parkinson
David B
DB
Moore
Philip K
PK
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000393:Air Pollutants / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D013440:Sulfides / Q000378:metabolism
D051698:Activating Transcription Factor 2; D000393:Air Pollutants; C497106:Atf2 protein, mouse; C529376:GYY 4137; D055551:HSP27 Heat-Shock Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D009946:Organothiophosphorus Compounds; D013440:Sulfides; C025451:sodium bisulfide; D006862:Hydrogen Sulfide