Cross-Talk Between NO and Arachidonic Acid in Inflammation

Abstract

Inducible nitric oxide synthase (iNOS) is expressed in a variety of cell types, in particular in inflammatory cells, in response to diverse pro-inflammatory stimuli. This process requires critical levels of arachidonic acid (AA), generated by constitutive phospholipase A(2) (PLA(2)), promoting tyrosine kinase-dependent phosphorylation, and inhibition, of constitutive NOS. Lowering basal NO levels is indeed critical for the activation of nuclear factor-kappaB (NF-kappaB), and thus for the expression of genes (e.g. iNOS) regulated by this transcription 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 NO might inhibit NF-kappaB activity in the same cells (e.g. astrocytes) in which it is generated, as well as in other cells that do not express constitutive NOS (e.g. microglia). NO from cells unable to respond to pro-inflammatory stimuli (e.g. neurons) will also contribute to these effects. Along the same line, AA released by pro-inflammatory molecules in specific cell types (e.g. astrocytes) might suppress constitutive NOS activity in the same cells as well as in other cells (e.g. neurons). 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 constitutive NOS) to pathological (i.e. mediated by iNOS). This second 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 summary, we suggest that the relative amounts of NO and AA, released by their constitutive enzymes, produce autocrine and paracrine effects regulating the onset of an inflammatory response in which, in addition to other factors, NO and AA are extensively released by their inducible enzymes.

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

“…The observations suggesting that the effects of hMSCs were mediated through microglia and/or macrophages are consistent with indications that both microglia and macrophages can be alternatively activated to play contrasting roles in response to injury (33)(34)(35). The increases in Gal-3 and Ym1 observed here provided a direct link between the effects of the hMSCs and activation of microglia or macrophages that may have been produced either by paracrines secreted by the hMSCs or by direct cell-to-cell contacts, as was observed during immunosuppression of T cells by MSCs (27).…”

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-.ALPHA.

“…These findings rule out the possibility of the involvement of NO or NOS in the protection afforded by LPS against HD cytotoxicity. NOS has been found to be induced in almost every model that involved an inflammatory response (Schafroth and Leuppi, 2007;Mariotto et al, 2007;Lozano and Gonzalez, 2007;Neeb and Reuter, 2007). HD-induced inflammation in RAW264.7 cells is one of the rare cases where NO is not involved.…”

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

“…All of the above-described phenotypic alterations may well be the result of alterations in the production, catabolism and/or function of eicosanoids: bioactive mediators derived from arachidonic acid via -6 fatty acids (including prostaglandins, prostacyclins, leukotrienes, thromboxanes, hepoxilins, and lipoxins) and bioactive mediators derived from eicosapentaenoic acid and docosahexaenoic acid via -3 fatty acids, (including resolvins, docosatrienes, eoxins, and neuroprotectins). Eicosanoids exert largely unappreciated complex control over virtually all physiological processes: inflammation (Chiang et al, 2005;Leone et al, 2007;Mariotto et al, 2007;Serhan, 2007;Seubert et al, 2007), resolution phase of inflammation (Serhan, 2007), innate immunity (Ballinger et al, 2007), cardiopulmonary and vascular functions (Moreland et al, 2007;Seubert et al, 2007), angiogenesis (Fleming, 2007;Inceoglu et al, 2007), sensor of vascular pO 2 (Sacerdoti et al, 2003), bowel motility (Proctor et al, 1987), regulation of lipid metabolism and insulin sensitivity (Larsen et al, 2007;Nigam et al, 2007;Spector and Norris, 2007), central nervous system functions (Miyata and Roman, 2005;Jakovcevic and Harder, 2007), modulation of non-neuropathic pain (Inceoglu et al, 2007), neurohormone secretion and release (Inceoglu et al, 2007), fibrinolysis (Westlund et al, 1991;Jiang, 2007), inhibition of platelet aggregation (Westlund et al, 1991;Jiang, 2007), reproductive success (Cha et al, 2006;Weems et al, 2006), blastocyst implantation (Cha et al, 2006;Kennedy et al, 2007), early embryonic as well as fetal development (Cha et al, 2006), stimulation of tyrosine phosphorylation (Chen et al, 1998), G protein-si...…”