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环境病理学,毒理学和肿瘤学期刊
影响因子: 1.625 5年影响因子: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN 打印: 0731-8898
ISSN 在线: 2162-6537

环境病理学,毒理学和肿瘤学期刊

DOI: 10.1615/JEnvironPatholToxicolOncol.v21.i2.30
10 pages

The Role of Nitric Oxide and Cyclooxygenase-2 in Attenuating Apoptosis

Bernhard Brune
University of Kaiserslautern, Faculty of Biology, Department of Cell Biology, Kaiserslautern, Germany
Andreas von Knethen
University of Kaiserslautern, Faculty of Biology, Department of Cell Biology, Kaiserslautern, Germany

ABSTRACT

The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome с relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 mM) or lipopolysaccharide/interferon-g/NG-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kВ as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kВ activation comprised p50/p65-heterodimer formation, IkВ degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kВ-site derived from the murine COX-2 promoter. A NF-kВ decoy approach (oligonucleotides directed against NF-kВ) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kВ and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).


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