title: Cyclooxygenase-2 is involved in HIV-1 Tat-induced inflammatory responses in the brain.
abstract: Cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoid synthesis, can be involved in inflammatory-mediated cytotoxicity. Although the contribution of COX-2 to peripheral inflammation is well understood, its role in brain inflammation is not fully recognized. In particular, COX-2 involvement in inflammatory responses induced by HIV proteins in the central nervous system is not known. Therefore, the present study focused on COX-2 expression and its role in modulating the expression of brain inflammatory-related genes following exposure to the HIV-1 transactivating protein Tat. Intrahippocampal injections of Tat induced dose-dependent upregulation of COX-2 mRNA and protein levels in C57BL/6 mice. COX-2 immunoreactivity was primarily localized in microglial cells and astrocytes. Tat-induced COX-2 expression was partially prevented by pyrrolidine dithiocarbamate, a potent antioxidant and an inhibitor of the transcription factor, nuclear factor kappaB. Most importantly, administration of the COX-2 inhibitor NS-398 attenuated Tat-mediated upregulation of mRNA and protein expression of inflammatory mediators, such as monocyte chemoattractant protein-1, interleukin-1beta, tumor necrosis factor-alpha, and inducible nitric oxide synthase. Moreover, treatment with NS-398 significantly attenuated Tat-induced activation of microglial cells. These results provide evidence that COX-2 overexpression can modulate induction of brain inflammatory mediators in response to HIV-1 Tat protein. Such alterations may play an important role in the development of brain inflammatory reactions in HIV-infected patients and contribute to the development of neurological complications in the course of HIV-1 infection.
authors.affiliation: Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky, Lexington KY 40536, USA.
authors.forename: Govinder
authors.initials: G
authors.lastname: Flora
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015971:Gene Expression Regulation, Enzymologic; D015696:Gene Products, tat / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D016861:Cyclooxygenase Inhibitors; D015696:Gene Products, tat; D016328:NF-kappa B; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D054322:tat Gene Products, Human Immunodeficiency Virus; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2