Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide.

Authors: Oh GS (1) , Pae HO (1) , Lee BS (1) , Kim BN (2) , Kim JM (2) , Kim HR (3) , Jeon SB (4) , Jeon WK (5) , Chae HJ (6) , Chung HT (1)
Affiliations:
(1) Medicinal Resources Research Institute, Wonkwang University, Department of Microbiology and Immunology, Wonkwang University School of Medicine (2) Department of Neurosurgery, Wonkwang University School of Medicine (3) Department of Dental Pharmacology and Wonkwang Dental Research Institute, Wonkwang University School of Dentistry (4) Department of Beauty Science, Sunghwa College (5) Department of Internal Medicine, Jong-ku (6) Department of Pharmacology and Institute of Cardiovascular Research, Chonbuk National University School of Medicine
Source: Free Radic Biol Med. 2006 Jul 1;41(1):106-19
DOI: 10.1016/j.freeradbiomed.2006.03.021 Publication date: 2006 Jul E-Publication date: April 25, 2006 Availability: abstract Copyright: © 2006 Elsevier Inc. All rights reserved.
Language: English Countries: Not specified Location: Not specified Correspondence address: Chung HT : htchung@wonkwang.ac.kr

Keywords

Article abstract

Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO.

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