The Effect of Hydrogen Sulfide Donors on Lipopolysaccharide-Induced Formation of Inflammatory Mediators in Macrophages

The role of hydrogen sulfide (H2S) in inflammation is controversial, with both pro-and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H2S, which give a rapid bolus of H2S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H2S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H2S 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-1 beta, IL-6, TNF-alpha, nitric oxide (center dot NO), and PGE(2) but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kappa B/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-1 beta, IL-6, NO, PGE(2) and TNF-alpha. This study clearly shows that the effects of H2S on the inflammatory process are complex and dependent not only on H2S concentration but also on the rate of H2S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro-versus antiinflammatory role of H2S. Antioxid. Redox Signal. 12, 1147-1154.