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ISSN Print: 0731-8898
ISSN Online: 2162-6537
Indexed in
The Role of Nitric Oxide and Cyclooxygenase-2 in Attenuating Apoptosis
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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