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Gene Review

NOS2  -  nitric oxide synthase 2, inducible

Homo sapiens

Synonyms: HEP-NOS, Hepatocyte NOS, INOS, Inducible NO synthase, Inducible NOS, ...
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Disease relevance of NOS2A

  • Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis [1].
  • Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria [2].
  • RESULTS: HSP patients exhibited a significantly increased frequency of the NOS2A short (8-11) CCTTTn alleles (OR 1.64, 95% CI 1.09-2.47, p=0.017) and genotypes (OR 3.59, 95% CI 1.79-7.20, p=0.0002) compared to controls, particularly when patients with nephritis were compared with controls [3].
  • OBJECTIVE: To assess the contribution of 2 polymorphisms within the inducible nitric oxide (NOS2A) promoter region to the susceptibility to Henoch-Schönlein purpura (HSP), and to determine if implications exist with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction (renal sequelae) [3].
  • OBJECTIVE: To assess the contribution of 2 polymorphisms within the inducible nitric oxide (NOS2A) promoter region to susceptibility to giant cell arteritis (GCA) [4].

Psychiatry related information on NOS2A


High impact information on NOS2A

  • Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction [10].
  • Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response [10].
  • NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone [11].
  • In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS) [11].
  • NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively [12].

Chemical compound and disease context of NOS2A


Biological context of NOS2A

  • Moreover, IL1R2 (P=0.002 in Blacks), NOS2A (P<0.001 in Whites) and OPRM1 (P=0.004 in Hispanics) gene haplotypes were associated with PTD in specific ethnic groups but not at global significance level [17].
  • In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families [1].
  • Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility [1].
  • NOS2A promoter genotype frequencies (n=715: 358 cases, 357 control subjects) were 0.3%, 16.8%, 83.0% and 0.3% 17.6% and 82.1% for +/+, +/- and -/- genotypes (p=0.952) [18].
  • Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR=2.2, 95% CI=1.1-4.4) (referent=Ser/Ser and Ser/Leu) [19].

Anatomical context of NOS2A

  • A significant gene-gene interaction between FCER1B 237Gly and NOS2A D346D was detected, with individuals carrying the minor allele for both polymorphisms having the lowest cord blood IL-13 levels [20].
  • Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients [21].
  • These findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells [22].
  • We conclude that inflammatory cytokines increase NOS activity in cultured human endothelial cells by increasing tetrahydrobiopterin levels in the face of falling total enzyme; similar regulation appears possible in vivo [23].
  • We have examined cytokine regulation of nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC) [23].

Associations of NOS2A with chemical compounds


Physical interactions of NOS2A

  • Nitric oxide, which is produced in metastases by three different NOS isozymes is capable of antagonizing the binding of FAK to matrix integrins [26].
  • In RNA binding studies TIAR displayed high affinity binding to the human iNOS 3'-UTR sequence [27].
  • Mapping of the binding site revealed KSRP interacting with the most 3'-located AU-rich element (ARE) of the human iNOS mRNA [28].
  • Interferon gamma (IFN-gamma) interacts synergistically with bacterial lipopolysaccharide (LPS) to induce transcription of iNOS, the isoform of nitric oxide synthase whose activity is independent of elevated Ca2+ and exogenous calmodulin [29].
  • In conclusion, using two cell systems, we demonstrated that the ETB receptor is functionally coupled to NOS and coordinates the generation of NO via a tyrosine kinase-dependent and a calcium/calmodulin-dependent pathway [30].

Enzymatic interactions of NOS2A


Co-localisations of NOS2A

  • Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart [32].
  • Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages [33].
  • Immunocytochemical double labeling revealed that both anti-iNOS immunoreactivity and anti-IL-1beta immunoreactivity colocalized with glial fibrillary acidic protein immunoreactivity in GBM [34].
  • Abeta colocalized with iNOS-expressing macrophages that were often surrounded by platelets [35].

Regulatory relationships of NOS2A

  • Interestingly, Stat 1 is repressive to basal and stimulated iNOS mRNA expression in 2fTGH human fibroblasts, which are refractory to iNOS induction [36].
  • Taken together, these results suggest that cav-1 promotes iNOS presence in detergent-insoluble membrane fractions and degradation there via the proteasome pathway [37].
  • Nitric-oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity [38].
  • Mutation of both these sites abrogated the KLF6-induced enhancement of the 0.63-kb iNOS promoter activity [39].
  • Finally, ET-1 is able to influence its own as well as NOS isoform expression in normal and PE trophoblastic cultured cells [40].

Other interactions of NOS2A

  • The release of NO and PGs by the inducible isoforms of NOS and COX has been associated with the pathological roles of these mediators in disease states as evidenced by the use of selective inhibitors [41].
  • Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders [42].
  • Ectopic expression of cav-1 in both cell lines correlated with significantly decreased iNOS activity and protein levels [37].
  • In human microglia, cytokines and LPS failed to induce NOS II expression, while the same stimuli readily induced TNF-alpha expression [43].
  • The inducing signals for astrocyte NOS II mRNA expression were in the order IL-1beta + IFN-gamma > IL-1beta + TNF-alpha > IL-1beta [43].

Analytical, diagnostic and therapeutic context of NOS2A


  1. Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis. Barcellos, L.F., Begovich, A.B., Reynolds, R.L., Caillier, S.J., Brassat, D., Schmidt, S., Grams, S.E., Walker, K., Steiner, L.L., Cree, B.A., Stillman, A., Lincoln, R.R., Pericak-Vance, M.A., Haines, J.L., Erlich, H.A., Hauser, S.L., Oksenberg, J.R. Ann. Neurol. (2004) [Pubmed]
  2. Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria. Burgner, D., Usen, S., Rockett, K., Jallow, M., Ackerman, H., Cervino, A., Pinder, M., Kwiatkowski, D.P. Hum. Genet. (2003) [Pubmed]
  3. Inducible nitric oxide synthase polymorphism is associated with susceptibility to Henoch-Schönlein purpura in northwestern Spain. Martin, J., Paco, L., Ruiz, M.P., Lopez-Nevot, M.A., Garcia-Porrua, C., Amoli, M.M., Calviño, M.C., Ollier, W.E., Gonzalez-Gay, M.A. J. Rheumatol. (2005) [Pubmed]
  4. Association of a functional inducible nitric oxide synthase promoter variant with susceptibility to biopsy-proven giant cell arteritis. Gonzalez-Gay, M.A., Oliver, J., Sanchez, E., Garcia-Porrua, C., Paco, L., Lopez-Nevot, M.A., Ollier, W.E., Martin, J. J. Rheumatol. (2005) [Pubmed]
  5. Nitric oxide synthase gene polymorphisms in Alzheimer's disease and dementia with Lewy bodies. Singleton, A.B., Gibson, A.M., McKeith, I.G., Ballard, C.G., Edwardson, J.A., Morris, C.M. Neurosci. Lett. (2001) [Pubmed]
  6. The pleiotropic effects of inducible nitric oxide synthase (iNOS) on the physiology and pathology of penile erection. Gonzalez-Cadavid, N.F., Rajfer, J. Curr. Pharm. Des. (2005) [Pubmed]
  7. Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation. Lüth, H.J., Münch, G., Arendt, T. Brain Res. (2002) [Pubmed]
  8. A novel genetic polymorphism of inducible nitric oxide synthase is associated with an increased risk of gastric cancer. Shen, J., Wang, R.T., Wang, L.W., Xu, Y.C., Wang, X.R. World J. Gastroenterol. (2004) [Pubmed]
  9. Increased HO-1 expression and decreased iNOS expression in the hippocampus from adult spontaneously hypertensive rats. Huang, Y., Wu, L., Xu, C., Yang, B., Wang, R. Cell Biochem. Biophys. (2006) [Pubmed]
  10. Nitric oxide and macrophage function. MacMicking, J., Xie, Q.W., Nathan, C. Annu. Rev. Immunol. (1997) [Pubmed]
  11. Nitric oxide in health and disease of the respiratory system. Ricciardolo, F.L., Sterk, P.J., Gaston, B., Folkerts, G. Physiol. Rev. (2004) [Pubmed]
  12. Free radicals in the physiological control of cell function. Dröge, W. Physiol. Rev. (2002) [Pubmed]
  13. Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. Brandi, M.L., Hukkanen, M., Umeda, T., Moradi-Bidhendi, N., Bianchi, S., Gross, S.S., Polak, J.M., MacIntyre, I. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  14. Role of nitric oxide in Sjögren's syndrome. Konttinen, Y.T., Platts, L.A., Tuominen, S., Eklund, K.K., Santavirta, N., Törnwall, J., Sorsa, T., Hukkanen, M., Polak, J.M. Arthritis Rheum. (1997) [Pubmed]
  15. Nitric oxide, iNOS, and inflammation in cystic fibrosis. Downey, D., Elborn, J.S. J. Pathol. (2000) [Pubmed]
  16. Estrogen induces nitric oxide production via activation of constitutive nitric oxide synthases in human neuroblastoma cells. Xia, Y., Krukoff, T.L. Endocrinology (2004) [Pubmed]
  17. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods. Hao, K., Wang, X., Niu, T., Xu, X., Li, A., Chang, W., Wang, L., Li, G., Laird, N., Xu, X. Hum. Mol. Genet. (2004) [Pubmed]
  18. Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Rippin, J.D., Patel, A., Belyaev, N.D., Gill, G.V., Barnett, A.H., Bain, S.C. Diabetologia (2003) [Pubmed]
  19. Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma. Wang, S.S., Davis, S., Cerhan, J.R., Hartge, P., Severson, R.K., Cozen, W., Lan, Q., Welch, R., Chanock, S.J., Rothman, N. Carcinogenesis (2006) [Pubmed]
  20. Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy. Hoffjan, S., Ostrovnaja, I., Nicolae, D., Newman, D.L., Nicolae, R., Gangnon, R., Steiner, L., Walker, K., Reynolds, R., Greene, D., Mirel, D., Gern, J.E., Lemanske, R.F., Ober, C. J. Allergy Clin. Immunol. (2004) [Pubmed]
  21. The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. Amin, A.R., Di Cesare, P.E., Vyas, P., Attur, M., Tzeng, E., Billiar, T.R., Stuchin, S.A., Abramson, S.B. J. Exp. Med. (1995) [Pubmed]
  22. IL-1 produced and released endogenously within human islets inhibits beta cell function. Arnush, M., Heitmeier, M.R., Scarim, A.L., Marino, M.H., Manning, P.T., Corbett, J.A. J. Clin. Invest. (1998) [Pubmed]
  23. Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. Rosenkranz-Weiss, P., Sessa, W.C., Milstien, S., Kaufman, S., Watson, C.A., Pober, J.S. J. Clin. Invest. (1994) [Pubmed]
  24. Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1. Tetsuka, T., Daphna-Iken, D., Srivastava, S.K., Baier, L.D., DuMaine, J., Morrison, A.R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  25. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Geller, D.A., Lowenstein, C.J., Shapiro, R.A., Nussler, A.K., Di Silvio, M., Wang, S.C., Nakayama, D.K., Simmons, R.L., Snyder, S.H., Billiar, T.R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  26. Expression of focal adhesion kinase (p125 FAK) and proline-rich tyrosine kinase 2 (PYK2/CAKb) in cerebral metastases, correlation with VEGF-R-, ecNOS III-labelling and morphometric data. Ludwig, H.C., Akhavan-Shigari, R., Rausch, S., Schallock, K., Quentin, C., Bockermann, V., Kolenda, H. Anticancer Res. (2000) [Pubmed]
  27. The RNA binding protein TIAR is involved in the regulation of human iNOS expression. Fechir, M., Linker, K., Pautz, A., Hubrich, T., Kleinert, H. Cell. Mol. Biol. (Noisy-le-grand) (2005) [Pubmed]
  28. Involvement of KSRP in the post-transcriptional regulation of human iNOS expression-complex interplay of KSRP with TTP and HuR. Linker, K., Pautz, A., Fechir, M., Hubrich, T., Greeve, J., Kleinert, H. Nucleic Acids Res. (2005) [Pubmed]
  29. Role of interferon regulatory factor 1 in induction of nitric oxide synthase. Martin, E., Nathan, C., Xie, Q.W. J. Exp. Med. (1994) [Pubmed]
  30. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. Tsukahara, H., Ende, H., Magazine, H.I., Bahou, W.F., Goligorsky, M.S. J. Biol. Chem. (1994) [Pubmed]
  31. Physiology and pathophysiology of nitric oxide. Ignarro, L.J. Kidney Int. Suppl. (1996) [Pubmed]
  32. Regulation of the mammalian heart function by nitric oxide. Massion, P.B., Pelat, M., Belge, C., Balligand, J.L. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. (2005) [Pubmed]
  33. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Baker, C.S., Hall, R.J., Evans, T.J., Pomerance, A., Maclouf, J., Creminon, C., Yacoub, M.H., Polak, J.M. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
  34. Association of elevated glial expression of interleukin-1beta with improved survival in patients with glioblastomas multiforme. Cuny, E., Loiseau, H., Penchet, G., Ellie, E., Arsaut, J., Vital, A., Vincendeau, P., Demotes-Mainard, J. J. Neurosurg. (2002) [Pubmed]
  35. Platelet phagocytosis and processing of beta-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. De Meyer, G.R., De Cleen, D.M., Cooper, S., Knaapen, M.W., Jans, D.M., Martinet, W., Herman, A.G., Bult, H., Kockx, M.M. Circ. Res. (2002) [Pubmed]
  36. Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Ganster, R.W., Taylor, B.S., Shao, L., Geller, D.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  37. Caveolin-1 down-regulates inducible nitric oxide synthase via the proteasome pathway in human colon carcinoma cells. Felley-Bosco, E., Bender, F.C., Courjault-Gautier, F., Bron, C., Quest, A.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  38. Nitric-oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity. Knudsen, G.M., Nishida, C.R., Mooney, S.D., Ortiz de Montellano, P.R. J. Biol. Chem. (2003) [Pubmed]
  39. Transcriptional activation of the human inducible nitric-oxide synthase promoter by Kruppel-like factor 6. Warke, V.G., Nambiar, M.P., Krishnan, S., Tenbrock, K., Geller, D.A., Koritschoner, N.P., Atkins, J.L., Farber, D.L., Tsokos, G.C. J. Biol. Chem. (2003) [Pubmed]
  40. Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms from normal and preeclamptic placentas. Napolitano, M., Miceli, F., Calce, A., Vacca, A., Gulino, A., Apa, R., Lanzone, A. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  41. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Mollace, V., Muscoli, C., Masini, E., Cuzzocrea, S., Salvemini, D. Pharmacol. Rev. (2005) [Pubmed]
  42. Distribution of nitric oxide synthase in normal and cirrhotic human liver. McNaughton, L., Puttagunta, L., Martinez-Cuesta, M.A., Kneteman, N., Mayers, I., Moqbel, R., Hamid, Q., Radomski, M.W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  43. Expression of type II nitric oxide synthase in primary human astrocytes and microglia: role of IL-1beta and IL-1 receptor antagonist. Liu, J., Zhao, M.L., Brosnan, C.F., Lee, S.C. J. Immunol. (1996) [Pubmed]
  44. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Asano, K., Chee, C.B., Gaston, B., Lilly, C.M., Gerard, C., Drazen, J.M., Stamler, J.S. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  45. Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study. Levecque, C., Elbaz, A., Clavel, J., Richard, F., Vidal, J.S., Amouyel, P., Tzourio, C., Alpérovitch, A., Chartier-Harlin, M.C. Hum. Mol. Genet. (2003) [Pubmed]
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