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

Abstract

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-1b, IL-6, TNF-a, nitric oxide ( NO), and PGE 2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kB=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-1b, IL-6, NO, PGE 2 and TNF-a. 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.

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…• NO, IL-1b and IL-6 and NF-kB activity, but higher concentrations of NaSH promoted the synthesis of pro inflammatory mediators [68]. Furthermore, in an in vivo murine model of acute arthritis induced by kaolin/ carrageenan [69], a bolus addition of 30-50 µM of Na 2 S inhibited leukocyte adhesion in postcapillary venules in acutely inflamed mouse knees.…”

“…While these salts are undoubtedly convenient and useful in that solutions of H 2 S (and HS -) can be readily prepared in the laboratory without the requirement for the use of awkward H 2 S gas cylinders, they are not particularly relevant tools to examine the physiology of H 2 S in vitro or in vivo. The addition of Na 2 S, NaSH or saturated solutions of H 2 S gas to aqueous solutions results in the instantaneous release of a bolus of H 2 S (and HS -), which dissipates in seconds [33,68]. It is highly unlikely that cells or tissues are ever exposed to H 2 S generated in such a rapid manner, generating high local concentrations of H 2 S, since endogenously produced H 2 S through CSE and CBS is relatively slow and sustained [68,92,109,110].…”

“…The addition of Na 2 S, NaSH or saturated solutions of H 2 S gas to aqueous solutions results in the instantaneous release of a bolus of H 2 S (and HS -), which dissipates in seconds [33,68]. It is highly unlikely that cells or tissues are ever exposed to H 2 S generated in such a rapid manner, generating high local concentrations of H 2 S, since endogenously produced H 2 S through CSE and CBS is relatively slow and sustained [68,92,109,110]. Furthermore, injection of these salts into animals results in a minimal increase in plasma H 2 S concentrations over a very short period of time [21,33,68,111].…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…For example, the slow-releasing H 2 S donor GYY4137 inhibited an LPS-induced proinflammatory response and increased expression of the anti-inflammatory chemokine IL-10, whereas rapid exposure to H 2 S produced from NaHS induced the opposite responses on the same type of cells (298). In addition, H 2 S effects can be species-and organ-specific, depending on differences in the activities of different H 2 S biosynthetic and catabolic pathways (290).…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…In most cases, GYY4137 reduces the functionality of inflammatory cells by inhibiting NF-κB signaling in the target cells. Thus, GYY4137 pretreatment reduces the secretion of proinflammatory mediators like interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), NO, and prostaglandin E 2 (PGE 2 ) (Whiteman et al, 2010) in mouse macrophages stimulated with LPS as well as in IL-8-stimulated airway smooth muscle cells (Perry et al, 2011). In human synoviocytes and articular chondrocytes, GYY4137 decreased LPS-evoked production of nitrite (NO 2 À ), PGE 2 , TNF-α, and IL-6 (Li, Fox, et al, 2013).…”