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Molecular Pharmacology

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Research ArticleArticle

Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo

Konstantin Tsoyi, Tae Yu Lee, Young Soo Lee, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee and Ki Churl Chang
Molecular Pharmacology July 2009, 76 (1) 173-182; DOI: https://doi.org/10.1124/mol.109.055137
Konstantin Tsoyi
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Tae Yu Lee
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Young Soo Lee
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Hye Jung Kim
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Han Geuk Seo
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Jae Heun Lee
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Ki Churl Chang
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Abstract

We examined our hypothesis that heme-oxygenase-1 (HO-1)-derived carbon monoxide (CO) inhibits the release of high-mobility group box 1 (HMGB1) in RAW264.7 cells activated with lipopolysaccharide (LPS) in vitro and in LPS- or cecal ligation and puncture (CLP)-induced septic mice in vivo, so that HO-1 induction or CO improves survival of sepsis in rodents. We found that pretreatment with HO-1 inducers (hemin, cobalt protoporphyrin IX) or transfection of HO-1 significantly inhibited HMGB1 release, which was blocked by HO-1 small interfering RNA, in cells activated by LPS. Carbon monoxide-releasing molecule 2 (CORM-2) but not bilirubin or deferoxamine inhibited HMGB1 release in LPS-activated macrophages. Oxyhemoglobin reversed the effect of HO-1 inducers on HMGB1 release. Translocation of HMGB1 from nucleus to cytosol was significantly inhibited by HO-1 inducers, CORM-2, or HO-1 transfection. Neutralizing antibodies to tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon-β, and Nω-nitro-l-arginine methyl ester hydrochloride but not N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) significantly inhibited HMGB1 release in LPS-activated cells. Production of TNF-α, IL-1β, and IFN-β was significantly reduced by pretreatment of HO-1 inducers, CORM-2, or HO-1 transfection in LPS-activated cells. Plasma levels of HMGB1 in mice challenged with LPS or CLP were significantly reduced by the administration of HO-1 inducers or CORM-2, which was accompanied by either reduction (pretreatment) or no change (delayed administration) of serum TNF-α and IL-1β levels. Regardless of pretreatment or delayed administration, CORM-2 and hemin rescued mice from lethal endotoxemia and sepsis induced by LPS or CLP. Taken together, we concluded that HO-1-derived CO reduces HMGB1 release in LPS-activated cells and LPS- or CLP-induced animal model of sepsis.

Footnotes

  • This work was supported by the Medical Research Council program of Ministry of Science and Technology/Korea Science and Engineering Foundation [Grant R13-2006-012-01003-0].

  • ABBREVIATIONS: HMGB1, high-mobility group box 1; HO-1, heme-oxygenase-1; CORM-2, carbon monoxide-releasing molecule II; LPS, lipopolysaccharide; CLP, cecal ligation and puncture; CoPPIX, cobalt protoporphyrin IX; COX, cyclooxygenase; DFO, deferoxamine mesylate; l-NAME, Nω-nitro-l-arginine methyl ester hydrochloride; iNOS, inducible nitric-oxide synthase; NS-398, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide; siRNA, small interfering RNA; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; INF-β, interferon-β; ELISA, enzyme-linked immunosorbent assay; HbO2, oxyhemoglobin; DMSO, dimethyl sulfoxide.

    • Accepted April 13, 2009.
    • Received January 28, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (1)
Molecular Pharmacology
Vol. 76, Issue 1
1 Jul 2009
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Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo
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Research ArticleArticle

Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo

Konstantin Tsoyi, Tae Yu Lee, Young Soo Lee, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee and Ki Churl Chang
Molecular Pharmacology July 1, 2009, 76 (1) 173-182; DOI: https://doi.org/10.1124/mol.109.055137

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Research ArticleArticle

Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo

Konstantin Tsoyi, Tae Yu Lee, Young Soo Lee, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee and Ki Churl Chang
Molecular Pharmacology July 1, 2009, 76 (1) 173-182; DOI: https://doi.org/10.1124/mol.109.055137
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