Biphasic induction of heme oxygenase-1 expression in macrophages stimulated with lipopolysaccharide |
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Authors: | Srisook Klaokwan Cha Young-Nam |
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Affiliation: | Department of Pharmacology and Toxicology, College of Medicine, Inha University, Incheon 400-103, Republic of Korea. |
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Abstract: | Time course relationship between inductions of iNOS and HO-1 was evaluated in RAW264.7 macrophages stimulated with LPS. Expression of HO-1 mRNA increased in a biphasic pattern, but that of xCT (cystine transporter) and iNOS mRNA increased in a monophasic manner. HO-1 protein level increased also in a biphasic manner, at 1-2 h and again between 8 and 24 h. However, iNOS protein began to increase at 4 h, quickly reaching a high level in a monophasic induction pattern. Production of NO* began to occur at 6 h and nitrite continued to accumulate in the culture medium. Total GSH level decreased markedly (50% of control) by 2 h, began to recover at 4 h, returned to control level by 6 h and increased above the control level during 10-24 h. Collectively, these results indicated that overproduced O2*- depletes GSH and triggers induction of xCT, HO-1, iNOS and HO-1 expression in sequence. Most notably, the second-phase induction of HO-1 was caused by overproduced NO*, resulting from LPS-derived iNOS induction. When this iNOS-derived delivery of NO* was combined with prior depletion of GSH using buthioninesulfoximine, an inhibitor of GSH biosynthesis, induction of HO-1 was potentiated. Furthermore, upon such super-induction of HO-1, NO* production was inhibited along with suppression of iNOS expression. Collectively, these results suggested that HO-1 is induced in a biphasic manner, sequentially by the overproduced O*2- and NO*, and the elevated HO-1 suppresses the production of these radicals in an auto-regulatory manner. This may allow the macrophages to survive from injuries that can be caused by concomitant oxidative and nitrosative stresses initiated by the LPS-driven oxidative burst. |
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Keywords: | O2 0" alt=" radical dot" src=" http://cdn.els-cdn.com/sd/entities/rad" class=" glyphImg" >−, superoxide anion NO 0" alt=" radical dot" src=" http://cdn.els-cdn.com/sd/entities/rad" class=" glyphImg" >, nitric oxide ONOO−, peroxynitrite CO, carbon monoxide HO-1, heme oxygenase-1 iNOS, inducible nitric oxide synthase xCT, cystine/glutamate exchange transporter GSH, reduced glutathione GSSG, oxidized glutathione LPS, lipopolysaccharide BSO, smallcaps" >dl-buthionine-[S,R]-sulfoximine ROS, reactive oxygen species smallcaps" >l-NAME, NG-nitro- smallcaps" >l-arginine methyl ester |
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