| Carbon monoxide from CORM-2 reduces HMGB1 release through regulation of IFN-β/JAK2/STAT-1/INOS/NO signaling but not COX-2 in TLR-activated macrophages. | |
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MedLine Citation:
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PMID: 20442692 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Reduction of high-mobility group box 1 (HMGB1) and NO levels may be important therapeutic strategy for treatment of sepsis. Recently, we found that carbon monoxide (CO) can reduce HMGB1 levels in septic animal models. Here, we tried to elucidate the molecular machinery of how CO inhibits HMGB1 release in toll-like receptor (TLR)-activated macrophages. Carbon monoxide-releasing molecule 2 (CORM-2) specifically inhibited the expression of iNOS (NO), but not of cyclooxygenase 2 (COX-2) (PGE₂) in RAW 264.7 cells activated either by peptidoglycan (TLR-2 agonist), polyinosinic-polycytidylic acid (TLR-3 agonist), or LPS (TLR-4 agonist); this inhibition seemed to be mediated via the JAK2/STAT1 pathway. Treatment with neutralizing antibody to IFN-β, a JAK2 inhibitor (AG490), or a STAT1 inhibitor (fludarabine) selectively inhibited iNOS, but not COX-2 in this system. Moreover, deletion of STAT1 by siRNA also showed preferential inhibition of iNOS but not COX-2 in LPS-treated cells. Carbon monoxide-releasing molecule 2 reduced IFN-β production and phosphorylation of JAK2 and STAT1 in LPS-activated RAW264.7 cells. Carbon monoxide-releasing molecule 2 failed to inhibit iNOS and HMGB1 levels in the presence of recombinant IFN-β and NO donor (NOC-18), respectively. Finally, plasma levels of HMGB1 and iNOS protein expression in lung tissues of cecal ligation and puncture-induced septic mice were decreased in the presence of CORM-2. Taken together, it is concluded that CO selectively inhibits iNOS over COX-2, at least through IFNβ/JAK2/STAT1 signals, and this regulation plays an important role in the CORM-2-mediated inhibitory effect on HMGB1 release in macrophages. |
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Authors:
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Konstantin Tsoyi; Irina Tsoy Nizamutdinova; Hwa Jin Jang; Lidiya Mun; Hye Jung Kim; Han Geuk Seo; Jae Heun Lee; Ki Churl Chang |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Shock (Augusta, Ga.) Volume: 34 ISSN: 1540-0514 ISO Abbreviation: Shock Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421564 Medline TA: Shock Country: United States |
Other Details:
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Languages: eng Pagination: 608-14 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, School of Medicine and Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang, Korea. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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