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

Abstract

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-1β, IL-6, TNF-α, nitric oxide (•NO), and PGE₂ but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-κB/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-1β, IL-6, NO, PGE₂ and TNF-α. 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.