Cyclooxygenase-2 is involved in HIV-1 Tat-induced inflammatory responses in the brain

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.