Cross-talk between NO and arachidonic acid in inflammation

Inducible nitric oxide synthase (iNOS) is expressed in a variety of cell types, in particular in inflammatory cells, inresponse to diverse pro-inflammatory stimuli. This process requires critical levels of arachidonic acid (AA), generated byconstitutive phospholipase A2 (PLA2), promoting tyrosine kinase-dependent phosphorylation, and inhibition, of constitutive NOS.Lowering basal NO levels is indeed critical for the activation of nuclear factor-κB (NF-κB), and thus for the expression of genes(e.g. iNOS) regulated by this trascription factor. It is interesting to note that NO and AA, two small lipid soluble molecules,rapidly cross the plasma membrane thereby allowing the triggering of the above responses in distal cells. That is, constitutive NOmight inhibit NF-κB activity in the same cells (e.g. astrocytes) in which it is generated, as well as in other cells that do not expressconstitutive NOS (e.g. microglia). NO from cells unable to respond to pro-inflammatory stimuli (e.g. neurons) will also contributeto these effects. Along the same line, AA released by pro-inflammatory molecules in specific cell types (e.g. astrocytes) mightsuppress constitutive NOS activity in the same cells as well as in other cells (e.g. neurons). Thus, AA produced at the very earlystages of the inflammatory response is a likely critical signal switching the regulation of the “NO tone” from physiological (i.e.mediated by constitutive NOS) to pathological (i.e. mediated by iNOS). This second phase of the inflammatory response is oftenaccompanied by the onset of deleterious effects in the tissue in which a critical role is played by iNOS-derived NO (directly orindirectly, i.e. via formation of peroxynitrite) as well as by products of the AA cascade. In summary, we suggest that the relativeamounts of NO and AA, released by their constitutive enzymes, produce autocrine and paracrine effects regulating the onset ofan inflammatory response in which, in addition to other factors, NO and AA are extensively released by their inducible enzymes.