A novel slow-releasing hydrogen sulfide donor, FW1256, exerts anti-inflammatory effects in mouse macrophages and in vivo.
Exogenous hydrogen sulfide (H2S) is known to exert anti-inflammatory effects both in macrophages and in animal models. In this study, we first showed that NaHS caused a concentration dependent reduction in TNFα and IL-6 secretion in LPS-stimulated RAW264.7 macrophages in the absence of cell death. Thereafter, we screened a series of novel slow H2S donors for similar activity. One such compound, FW1256, concentration dependently decreased TNFα, IL-6, PGE2and NO generation in LPS-stimulated RAW264.7 macrophages and BMDMs. FW1256 also significantly reduced IL-1β, COX-2 and iNOS mRNA and protein in LPS-stimulated RAW264.7 macrophages. Mechanistically, FW1256 decreased NFκB activation as evidenced by reduced cytosolic phospho-IκBα levels and reduced nuclear p65 levels in LPS-stimulated RAW264.7 macrophages treated with FW1256. Using a H2S fluorescent probe in FW1256-treated RAW264.7 macrophages, H2S release from FW1256 was apparent over a period of 24h in these cells. Moreover, the effect of FW1256 on TNFα and IL-6 by FW1256 in LPS-stimulated RAW264.7 macrophages was reversed by treatment with the H2S scavenger, vitamin B12a. FW1256 had no cytotoxic effect on LPS-stimulated RAW264.7 macrophages or BMDMs. In vivo, FW1256 administration also reduced IL-1β, TNFα, nitrate/nitrite and PGE2levels in LPS-treated mice. We show here a novel slow H2S-releasing compound that exerts anti-inflammatory effects in macrophages and in vivo. FW1256 may be a useful tool to study the biological effects of exogenous H2S and could also have future therapeutic value in inflammatory conditions.
Department of Pharmacology, UHL Level 5-02R, Lee Kong Chian Wing, 21 Lower Kent Ridge Road, National University of Singapore, 119077, Singapore; NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, 117456, Singapore; Department of Neurobiology, National University of Singapore, Centre for Life Sciences (CeLS), 28 Medical Drive, #04-21, 117456, Singapore.
Caleb Weihao
CW
Huang
Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
Wei
W
Feng
Department of Pharmacology, UHL Level 5-02R, Lee Kong Chian Wing, 21 Lower Kent Ridge Road, National University of Singapore, 119077, Singapore; Department of Neurobiology, National University of Singapore, Centre for Life Sciences (CeLS), 28 Medical Drive, #04-21, 117456, Singapore.
Meng Teng
MT
Peh
Department of Chemistry, Block S8 Level 3, Science Drive 3, National University of Singapore, 117543, Singapore.
Kaye
K
Peh
Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
Brian W
BW
Dymock
Department of Pharmacology, UHL Level 5-02R, Lee Kong Chian Wing, 21 Lower Kent Ridge Road, National University of Singapore, 119077, Singapore; Department of Neurobiology, National University of Singapore, Centre for Life Sciences (CeLS), 28 Medical Drive, #04-21, 117456, Singapore. Electronic address: dprmpk@nus.edu.sg.
Philip Keith
PK
Moore
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D006862:Hydrogen Sulfide
H(2)S donors; Hydrogen sulfide; Inflammation; Macrophages; Slow-releasing H(2)S donors