Inducible nitric oxide synthase (iNOS) is expressed in several cell types, particularly in inflammatory cells, in response to diverse proinflammatory stimuli, including
viral proteins as HIV Tat and gp120. This response is preceded by an early decline in basal
nitric oxide (NO) levels, dependent on a signaling leading to inhibition of the constitutive
isoform of
NO synthase (cNOS). This process requires critical levels of
arachidonic acid (AA), generated by Ca<sup>2+</sup>-dependent activation of cytosolic
phospholipase A2, and is mediated by the downstream
tyrosine kinase-dependent phosphorylation of cNOS. Lowering basal NO levels are necessary for the activation of nuclear factor-κB, and thus for the expression of a variety of genes regulated by this
transcription factor, which include iNOS. Notably, NO and AA, two small
lipid soluble molecules, can trigger the above responses also in distal cells. Thus, AA produced at the very early stages of the inflammatory response is a likely critical signal switching the regulation of the "NO tone" from physiological (i.e., mediated by cNOS) to pathological (i.e., mediated by iNOS). This later phase of the inflammatory response is often accompanied by the onset of deleterious effects in the tissue, in which a critical role is played by iNOS-derived NO (directly or indirectly, i.e., via formation of
peroxynitrite) as well as by products of the AA cascade. In this review, the authors discuss the implications of the crosstalk between the NOS
isoforms in HIV-associated neuro-pathogenesis highlighting the role of NO and AA as mediators of cytotoxicity.