Previous reports have shown that the human immunodeficiency virus (HIV) regulatory
protein Tat has both
pro-oxidant and pro-inflammatory properties, suggesting that Tat might contribute to the neurological complications of HIV. However, the intracellular mechanisms whereby Tat triggers
free radical production and
inflammation, and the relationship between Tat-induced
free radicals and inflammatory reactions, are still subject to debate. The present study was undertaken to evaluate the specific effects of Tat on
NADPH oxidase in microglia and macrophages, and to determine the specific role of
NADPH oxidase in Tat-induced
cytokine/
chemokine release and neurotoxicity. Application of Tat to microglia or macrophages caused dose- and time-dependent increases in
superoxide formation that were prevented by both pharmacologic
NADPH oxidase inhibitors and by specific decoy
peptides (gp91ds). Furthermore, inhibition of
NADPH oxidase attenuated Tat-induced release of
interleukin-6 (IL-6),
tumor necrosis factor alpha (TNF), and
monocyte chemoattractant protein 1 (MCP-1), and decreased microglial-mediated neurotoxicity. Finally, macrophages derived from
NADPH oxidase-deficient mice displayed reduced
superoxide production, released lower levels of
cytokines/
chemokines, and induced less neurotoxicity in response to Tat compared to wild-type macrophages. Together, these data describe a specific and biologically significant signaling component of the macrophage/microglial response to Tat, and suggest the neuropathology associated with
HIV infection might originate in part with Tat-induced activation of
NADPH oxidase.