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Gene Review

Nos2  -  nitric oxide synthase 2, inducible

Mus musculus

Synonyms: Inducible NO synthase, Inducible NOS, Inosl, MAC-NOS, Macrophage NOS, ...
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Disease relevance of Nos2


Psychiatry related information on Nos2


High impact information on Nos2

  • Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death [10].
  • Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro [10].
  • Moreover, mice in which the gene encoding iNOS was disrupted (Nos2-/- mice) are protected from high-fat-induced insulin resistance [11].
  • Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat [11].
  • These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity [11].

Chemical compound and disease context of Nos2


Biological context of Nos2

  • Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox-2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis [1].
  • CONCLUSION/INTERPRETATION: Although the Nitric Oxide Synthase 2 ( Nos2) gene, localized at 45.6 cM in chromosome 11, is a good candidate gene, our results suggest that Nitric Oxide Synthase 2 activation might not be a crucial event for streptozotocin-induced destruction of pancreatic beta cells [17].
  • Mice lacking Nos2 did not show changes in tumorigenesis or nitrotyrosine formation, while demonstrating an arginine-dependent increase in apoptosis [18].
  • In ovarian macrophages, inducible nitric oxide synthase (Nos2), an important proinflammatory enzyme that regulates ovulation, was significantly reduced by troglitazone treatment, an effect that was restricted to cells from the preovulatory ovary [19].
  • We sought to investigate the influence of the inducible (Nos2) and endothelial (Nos3) NOS genes as a function of genetic background on ovulatory capacity and early embryonic development in a mouse model [20].

Anatomical context of Nos2


Associations of Nos2 with chemical compounds

  • Despite the fact that MOLF/Ei mice have the ability to respond to LPS and the fact that there are significant increases in IL-1 alpha and IL-1 beta mRNA, Nos2 in the spleen is not upregulated and nitrite production by spleen cells is reduced [24].
  • We investigated dietary arginine-induced intestinal tumorigenesis and NSAID-inhibitory effects in Apc(Min/+) mice differentially expressing nitric oxide synthase-2 (Nos2) [12].
  • The activation of Nos2 was accompanied by an increase in the fluorescence of 4,5-diaminofluorescein diacetate, a nitric oxide trap, and accumulation of 3-nitrotyrosine within cellular proteins in a dose-dependent manner [21].
  • These effects were inhibited by actinomycin D and by N-[3-(aminomethyl)benzyl]acetamidine dihydrochloride, a specific inhibitor of Nos2 [21].
  • We next conducted electophoretic mobility shift assay (EMSA) to determine the DNA binding activity of nuclear factor kappa B (Nfkappab), an important upstream modulator for Nos2 expression, to find that fluoxetine increased DNA binding activity of Nfkappab [25].
  • Other geographically distant AP-1 and NF-kappaB sites are certainly occupied, but selected sites are critical for iNOS transcription and the formation of the c-Jun, p65, and p300 transcriptional complex [26].

Physical interactions of Nos2


Regulatory relationships of Nos2

  • Moreover, we show that HuR regulates iNOS expression in an AMP-activated protein kinase (AMPK)-dependent manner [4].
  • Furthermore, tyrphostin inhibited the promoter activation of iNOS gene induced by IFN-gamma plus LPS, and it also suppressed IFN-gamma plus LPS-induced nuclear factor-kappa B-binding activity but not AP-1-binding activity [32].
  • Role of interferon regulatory factor-1 in double-stranded RNA-induced iNOS expression by mouse islets [33].
  • These data indicate that absence of iNOS causes enhanced lung inflammatory responses in mice which may be related to enhanced production of MCP-1 by endothelial cells and macrophages [34].
  • The effect of flagellin on iNOS gene expression was inhibited by a Stat1 mutant protein [35].

Other interactions of Nos2


Analytical, diagnostic and therapeutic context of Nos2

  • The mRNA level of nitric oxide synthase (iNos, Nos2) by RT-PCR was also stimulated by fluoxetine [25].
  • The goal of this study was to interrogate the role of inducible NO synthase (iNOS) in the late phase of ischemic preconditioning (PC) in vivo [3].
  • Angiogenesis, vessel diameter, blood flow rate, and vascular permeability were proportional to NO levels measured with microelectrodes: Wild-type (WT) > or = WT with l-NIL or iNOS(-/-) > eNOS(-/-) > or = eNOS(-/-) with l-NIL [38].
  • Western blotting analysis revealed that, after coculture, iNOS protein was up-regulated 55-fold more than the control in JB6 P+ but not in P- cells [39].
  • Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A) [40].


  1. Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse. Scott, D.J., Hull, M.A., Cartwright, E.J., Lam, W.K., Tisbury, A., Poulsom, R., Markham, A.F., Bonifer, C., Coletta, P.L. Gastroenterology (2001) [Pubmed]
  2. Lethal Mycobacterium bovis Bacillus Calmette Guérin infection in nitric oxide synthase 2-deficient mice: cell-mediated immunity requires nitric oxide synthase 2. Garcia, I., Guler, R., Vesin, D., Olleros, M.L., Vassalli, P., Chvatchko, Y., Jacobs, M., Ryffel, B. Lab. Invest. (2000) [Pubmed]
  3. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Guo, Y., Jones, W.K., Xuan, Y.T., Tang, X.L., Bao, W., Wu, W.J., Han, H., Laubach, V.E., Ping, P., Yang, Z., Qiu, Y., Bolli, R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  4. NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. Di Marco, S., Mazroui, R., Dallaire, P., Chittur, S., Tenenbaum, S.A., Radzioch, D., Marette, A., Gallouzi, I.E. Mol. Cell. Biol. (2005) [Pubmed]
  5. Exogenous nitric oxide regulates IFN-gamma plus lipopolysaccharide-induced nitric oxide synthase expression in mouse macrophages. Sheffler, L.A., Wink, D.A., Melillo, G., Cox, G.W. J. Immunol. (1995) [Pubmed]
  6. Phagocytosis is regulated by nitric oxide in murine microglia. Kopec, K.K., Carroll, R.T. Nitric Oxide (2000) [Pubmed]
  7. Expression of inducible nitric oxide synthase in the brains of scrapie-infected mice. Ju, W.K., Park, K.J., Choi, E.K., Kim, J., Carp, R.I., Wisniewski, H.M., Kim, Y.S. J. Neurovirol. (1998) [Pubmed]
  8. Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice. Itzhak, Y., Martin, J.L., Ali, S.F. Synapse (1999) [Pubmed]
  9. Minocycline in Huntington's disease: a pilot study. Thomas, M., Ashizawa, T., Jankovic, J. Mov. Disord. (2004) [Pubmed]
  10. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. MacMicking, J.D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D.S., Trumbauer, M., Stevens, K., Xie, Q.W., Sokol, K., Hutchinson, N. Cell (1995) [Pubmed]
  11. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Perreault, M., Marette, A. Nat. Med. (2001) [Pubmed]
  12. Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival. Zell, J.A., Ignatenko, N.A., Yerushalmi, H.F., Ziogas, A., Besselsen, D.G., Gerner, E.W., Anton-Culver, H. Int. J. Cancer (2007) [Pubmed]
  13. Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-deficient mice. Gühring, H., Görig, M., Ates, M., Coste, O., Zeilhofer, H.U., Pahl, A., Rehse, K., Brune, K. J. Neurosci. (2000) [Pubmed]
  14. Increased mortality, blunted production of nitric oxide, and increased production of TNF-alpha in endotoxemic TGF-beta1 transgenic mice. Vodovotz, Y., Kopp, J.B., Takeguchi, H., Shrivastav, S., Coffin, D., Lucia, M.S., Mitchell, J.B., Webber, R., Letterio, J., Wink, D., Roberts, A.B. J. Leukoc. Biol. (1998) [Pubmed]
  15. Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis. Sahrbacher, U.C., Lechner, F., Eugster, H.P., Frei, K., Lassmann, H., Fontana, A. Eur. J. Immunol. (1998) [Pubmed]
  16. Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood-brain barrier breakdown. Winkler, F., Koedel, U., Kastenbauer, S., Pfister, H.W. J. Infect. Dis. (2001) [Pubmed]
  17. Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes. Gonzalez, C., Cuvellier, S., Hue-Beauvais, C., Lévi-Strauss, M. Diabetologia (2003) [Pubmed]
  18. The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis. Yerushalmi, H.F., Besselsen, D.G., Ignatenko, N.A., Blohm-Mangone, K.A., Padilla-Torres, J.L., Stringer, D.E., Cui, H., Holubec, H., Payne, C.M., Gerner, E.W. Mol. Carcinog. (2006) [Pubmed]
  19. Troglitazone regulates peroxisome proliferator-activated receptors and inducible nitric oxide synthase in murine ovarian macrophages. Minge, C.E., Ryan, N.K., Van Der Hoek, K.H., Robker, R.L., Norman, R.J. Biol. Reprod. (2006) [Pubmed]
  20. Inducible and endothelial nitric oxide synthase: genetic background affects ovulation in mice. Hefler, L.A., Gregg, A.R. Fertil. Steril. (2002) [Pubmed]
  21. Activation of the nitric oxide synthase 2 pathway in the response of bone marrow stromal cells to high doses of ionizing radiation. Gorbunov, N.V., Pogue-Geile, K.L., Epperly, M.W., Bigbee, W.L., Draviam, R., Day, B.W., Wald, N., Watkins, S.C., Greenberger, J.S. Radiat. Res. (2000) [Pubmed]
  22. Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Hewett, S.J., Csernansky, C.A., Choi, D.W. Neuron (1994) [Pubmed]
  23. NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis. Hatano, E., Bennett, B.L., Manning, A.M., Qian, T., Lemasters, J.J., Brenner, D.A. Gastroenterology (2001) [Pubmed]
  24. Host immune response to Salmonella enterica serovar Typhimurium infection in mice derived from wild strains. Sebastiani, G., Blais, V., Sancho, V., Vogel, S.N., Stevenson, M.M., Gros, P., Lapointe, J.M., Rivest, S., Malo, D. Infect. Immun. (2002) [Pubmed]
  25. Fluoxetine increases the nitric oxide production via nuclear factor kappa B-mediated pathway in BV2 murine microglial cells. Ha, E., Jung, K.H., Choe, B.K., Bae, J.H., Shin, D.H., Yim, S.V., Baik, H.H. Neurosci. Lett. (2006) [Pubmed]
  26. Characterization of short range DNA looping in endotoxin-mediated transcription of the murine inducible nitric-oxide synthase (iNOS) gene. Guo, H., Mi, Z., Kuo, P.C. J. Biol. Chem. (2008) [Pubmed]
  27. Complex formation of the interferon (IFN) consensus sequence-binding protein with IRF-1 is essential for murine macrophage IFN-gamma-induced iNOS gene expression. Xiong, H., Zhu, C., Li, H., Chen, F., Mayer, L., Ozato, K., Unkeless, J.C., Plevy, S.E. J. Biol. Chem. (2003) [Pubmed]
  28. Regulation of cytokine-induced iNOS expression by a hairpin oligonucleotide in murine cerebral endothelial cells. Xu, J., Wu, Y., He, L., Yang, Y., Moore, S.A., Hsu, C.Y. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  29. Polysaccharide isolated from Poria cocos sclerotium induces NF-kappaB/Rel activation and iNOS expression through the activation of p38 kinase in murine macrophages. Lee, K.Y., You, H.J., Jeong, H.G., Kang, J.S., Kim, H.M., Rhee, S.D., Jeon, Y.J. Int. Immunopharmacol. (2004) [Pubmed]
  30. Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase. Minamoto, K., Harada, H., Lama, V.N., Fedarau, M.A., Pinsky, D.J. J. Exp. Med. (2005) [Pubmed]
  31. Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression. Fritsche, G., Dlaska, M., Barton, H., Theurl, I., Garimorth, K., Weiss, G. J. Immunol. (2003) [Pubmed]
  32. Roles of tyrosine kinases in the regulation of nitric oxide synthesis in murine liver cells: modulation of NF-kappa B activity by tyrosine kinases. Lee, B.S., Kang, H.S., Pyun, K.H., Choi, I. Hepatology (1997) [Pubmed]
  33. Role of interferon regulatory factor-1 in double-stranded RNA-induced iNOS expression by mouse islets. Blair, L.A., Maggi, L.B., Scarim, A.L., Corbett, J.A. J. Biol. Chem. (2002) [Pubmed]
  34. Regulatory effects of iNOS on acute lung inflammatory responses in mice. Speyer, C.L., Neff, T.A., Warner, R.L., Guo, R.F., Sarma, J.V., Riedemann, N.C., Murphy, M.E., Murphy, H.S., Ward, P.A. Am. J. Pathol. (2003) [Pubmed]
  35. Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes. Mizel, S.B., Honko, A.N., Moors, M.A., Smith, P.S., West, A.P. J. Immunol. (2003) [Pubmed]
  36. Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice. Carrera, L., Gazzinelli, R.T., Badolato, R., Hieny, S., Muller, W., Kuhn, R., Sacks, D.L. J. Exp. Med. (1996) [Pubmed]
  37. Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection. Räisänen-Sokolowski, A., Mottram, P.L., Glysing-Jensen, T., Satoskar, A., Russell, M.E. J. Clin. Invest. (1997) [Pubmed]
  38. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Fukumura, D., Gohongi, T., Kadambi, A., Izumi, Y., Ang, J., Yun, C.O., Buerk, D.G., Huang, P.L., Jain, R.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  39. Nitric oxide synthase is induced in tumor promoter-sensitive, but not tumor promoter-resistant, JB6 mouse epidermal cells cocultured with interferon-gamma-stimulated RAW 264.7 cells: the role of tumor necrosis factor-alpha. Murakami, A., Kawabata, K., Koshiba, T., Gao, G., Nakamura, Y., Koshimizu, K., Ohigashi, H. Cancer Res. (2000) [Pubmed]
  40. In vivo regulation of inducible no synthase in immune-mediated liver injury in mice. Koerber, K., Sass, G., Kiemer, A.K., Vollmar, A.M., Tiegs, G. Hepatology (2002) [Pubmed]
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