The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.
Bottom Line: We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro.GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro.In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA.
Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.Show MeSH
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Mentions: Treatment of HFLS (Fig. 1) or HAC (Fig. 2) with LPS significantly increased the levels of PGE2 [A], TNF-α [B], IL-6 [C] and •NO (measured as NO2−) [D] in culture supernatant of both joint cell types. Treatment of HFLS (Fig. 1A–D) or HAC (Fig. 2A–D) with GYY4137 (100–500 μM) for 1 hr prior to stimulation significantly reduced the levels of pro-inflammatory mediators in culture supernatant. Similarly, GYY4137 (>100 μM) significantly inhibited the increase in •NO (Fig. 1E) and PGE2 (Fig. 1F) levels induced by a cocktail of TNF-α (10 ng/ml), interleukin-1 beta (IL-1β; 1 ng/ml) and interferon-gamma (IFN-γ; 10 ng/ml).
Affiliation: Pharmaceutical Science Research Division, King's College London, London, England.