Affinage

NOS2

Nitric oxide synthase, inducible · UniProt P35228

Length
1153 aa
Mass
131.1 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOS2 (inducible nitric oxide synthase) is a cytokine- and pathogen-inducible enzyme that synthesizes nitric oxide (NO) from L-arginine to drive inflammatory, immunometabolic, and tissue-remodeling programs (PMID:8577713, PMID:35978195). Its expression is normally absent or low and is induced transcriptionally by pro-inflammatory cytokines (TNFα, IL-1β, IFNγ) acting through distal 5' regulatory regions of the human gene (PMID:8577713), with C/EBPβ identified as a required promoter-binding activator (PMID:10844594) and STAT1 and NF-κB cooperating to amplify induction, for example when IL-17 augments IFNγ signaling (PMID:26677135). Diverse upstream inputs converge on this control: NOD1/Rip2 and TLR4 signaling (PMID:20649597), TLR7-sensed bacterial RNA in microglial phagosomes (PMID:32554491), NLRC4/caspase-1-mediated PARP1 cleavage that opens chromatin at NF-κB sites (PMID:28150715), Sur1-Trpm4/Ca2+/calcineurin-NFAT signaling (PMID:27246103), and HIF-1α/BRD4-driven glycolysis that stabilizes Nos2 mRNA (PMID:37820788); conversely, tristetraprolin binds AU-rich elements in the Nos2 3'UTR to suppress its expression (PMID:31595002), and NOS2-derived NO S-nitrosylates NF-κB p65 to reduce NOS2 promoter occupancy, forming a negative-feedback loop (PMID:17720813). Downstream, NOS2 acts as a hub of inflammatory effector functions: its L-citrulline product is channeled by LACC1 to ornithine and polyamine immunometabolism via ODC1 in macrophages (PMID:35978195), its NO supports antibacterial killing and Th17 induction through cGMP-cGK signaling (PMID:23797095, PMID:37820788), and it links to a feed-forward NOS2/COX2 loop and aggressive phenotypes in breast cancer (PMID:29087320, PMID:24733928). NO further drives p53-dependent apoptosis in cardiac allograft rejection (PMID:9989972) and NO/p38-MAPK/KAT5-mediated DNMT1 degradation causing DNA hypomethylation and epithelial transformation (PMID:35584114). Inherited autosomal recessive NOS2 deficiency in humans causes fatal CMV infection while sparing control of most other pathogens, defining a non-redundant role in anti-CMV immunity (PMID:31995689).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1996 High

    Established that the human NOS2 gene is transcriptionally inducible by inflammatory cytokines and mapped the responsive elements to distal upstream regions, distinguishing human regulation from the murine macrophage promoter.

    Evidence Nuclear run-on and deletion-mapped luciferase reporters in human liver epithelial cells stimulated with TNFα/IL-1β/IFNγ

    PMID:8577713

    Open questions at the time
    • Did not identify the specific transcription factors binding the distal regions
    • Functional relevance in immune cell types not addressed
  2. 1998 High

    Defined a downstream consequence of NOS2 activity by showing NO selectively suppresses specific cytochrome P450 catalytic activities during endotoxemia, separating NO-dependent from NO-independent P450 regulation.

    Evidence NOS2 knockout mice and aminoguanidine in an LPS endotoxemia model with P450 activity and expression assays

    PMID:9687568

    Open questions at the time
    • Molecular mechanism of NO action on P450 enzymes not resolved
    • Limited to a subset of P450 isoforms
  3. 1999 Medium

    Identified a cis-acting polymorphic element by showing the promoter (CCTTT)n pentanucleotide repeat modulates IL-1β-inducible NOS2 transcription in an allele-length-dependent manner.

    Evidence Luciferase reporter assays with varying (CCTTT)n repeat constructs in colonic carcinoma cells

    PMID:10506586

    Open questions at the time
    • Single cell line, single reporter method
    • Trans-acting factor binding the repeat not identified
  4. 2000 High

    Identified C/EBPβ as a required transcriptional activator of NOS2 and a target of anti-inflammatory α-MSH, defining a specific factor distinct from NF-κB.

    Evidence EMSA/supershift and promoter-luciferase assays with C/EBP box deletion/mutation in RAW 264.7 macrophages

    PMID:10844594

    Open questions at the time
    • How α-MSH signaling reaches C/EBPβ DNA binding not detailed
    • Macrophage cell line only
  5. 2001 High

    Demonstrated post-translational control of NOS2 abundance by showing an S714P mutation shortens protein half-life without affecting mRNA, implicating proteasomal degradation.

    Evidence Mutant NOS2 transfection in COS-7 cells with metabolic labeling and nitrite assays

    PMID:11509447

    Open questions at the time
    • Specific degradation machinery (E3 ligase) not identified
    • Findings derived from a rat salt-sensitive allele in a heterologous cell line
  6. 2004 High

    Connected NOS2 to apoptotic tissue injury by showing NO drives p53-dependent apoptosis during cardiac allograft rejection independently of Fas and TNF pathways.

    Evidence NOS2 knockout recipients in a heterotopic cardiac transplant model with multiple apoptosis readouts

    PMID:9989972

    Open questions at the time
    • Direct molecular link between NO and p53 induction not defined
    • Cell type executing apoptosis not specified
  7. 2004 Medium

    Showed NOS2 induction can be amplified by mitochondrial ROS via the NIK/NF-κB axis, broadening the upstream signals controlling NOS2.

    Evidence Dominant-negative IκBα/NIK and mitochondrial antioxidant MitoQ with NF-κB gel shifts in C6 glioma cells

    PMID:15010209

    Open questions at the time
    • Single cell line and stimulus (manganese)
    • Physiological relevance beyond metal exposure unclear
  8. 2006 High

    Placed NOS2 downstream of TLR4/MyD88 as a pro-survival effector in cardiomyocytes, expanding NOS2 function beyond cytotoxic inflammation.

    Evidence TLR4-/-, MyD88-/- and NOS2 inhibition in isolated cardiomyocytes under serum deprivation apoptosis

    PMID:16648192

    Open questions at the time
    • Downstream survival signaling from NO not mapped
    • Context dependence of pro-survival vs pro-apoptotic NO unresolved
  9. 2007 High

    Revealed a negative-feedback mechanism by which NOS2-derived NO S-nitrosylates NF-κB p65 to reduce NOS2 promoter occupancy, allowing the enzyme to limit its own induction.

    Evidence p65 cysteine mutagenesis, S-nitrosylation detection, NF-κB reporters and NOS2 promoter ChIP in epithelial cells and macrophages

    PMID:17720813

    Open questions at the time
    • Quantitative contribution of feedback to physiological NO output not established
    • Other S-nitrosylation targets in the pathway not assessed
  10. 2010 Medium

    Distinguished cell-type-specific upstream pathways, identifying NOD1/Rip2 as dominant for NOS2 induction in vascular smooth muscle versus TLR4/caspase/PKC in macrophages, both converging on NF-κB/MAPK.

    Evidence Systematic pharmacological inhibitor dissection in vascular smooth muscle cells versus macrophages

    PMID:20649597

    Open questions at the time
    • Inhibitor-based, no genetic confirmation
    • Single lab, two cell types
  11. 2013 High

    Defined an effector role for NOS2 in adaptive immunity by showing endogenous NOS2 and downstream cGMP-cGK signaling are required for human Th17 induction and stability.

    Evidence NOS2 and cGMP-cGK pathway inhibition in human naive, memory, and tumor-infiltrating CD4+ T cells

    PMID:23797095

    Open questions at the time
    • Molecular targets of cGK driving IL-17 not identified
    • Mainly pharmacological inhibition
  12. 2014 High

    Mapped basal versus inflammatory NOS2-expressing cell types in brain, showing scattered neuronal expression at baseline and inducible microglial expression under inflammation.

    Evidence Nos2 promoter-driven lineage-tracing transgenic mice with immunohistochemistry under basal and LPS+IFNγ conditions

    PMID:24615726

    Open questions at the time
    • Functional role of basal neuronal NOS2 not addressed
    • Mouse data only
  13. 2014 High

    Established NOS2 as a driver of aggressive tumor phenotype, with NO induced by hypoxia/IFNγ and feed-forward NO promoting migration, chemoresistance, and metastasis in ER-negative breast cancer.

    Evidence NOS2 inhibition with multiple stimuli and in vivo xenograft/brain metastasis models in MDA-MB-231 cells

    PMID:24733928

    Open questions at the time
    • Direct molecular targets of NO driving each phenotype not fully resolved
    • Cell-line-restricted models
  14. 2015 Medium

    Showed NO regulates epithelial barrier integrity and inflammatory tone by transcriptionally downregulating ZO-1 and shaping macrophage polarization and NF-κB activity in lung injury.

    Evidence NOS2 inhibitor and NOS2-/- mice in a bleomycin lung injury model with ZO-1 and NF-κB readouts

    PMID:26526764

    Open questions at the time
    • Mechanism linking NO to ZO-1 transcription unresolved
    • Single lab
  15. 2015 Medium

    Showed IL-17 cooperates with IFNγ to intensify NOS2 transcription by enhancing STAT1 phosphorylation and NF-κB binding at the NOS2 promoter.

    Evidence Phospho-signaling Western blots, NOS2 promoter ChIP, and inhibitors in RAW 264.7 macrophages

    PMID:26677135

    Open questions at the time
    • Single cell line
    • Relative contributions of STAT1 vs NF-κB not quantified
  16. 2016 High

    Identified Sur1-Trpm4/Ca2+-calcineurin-NFAT signaling as an upstream controller of Nos2 transcription in TLR4-activated microglia.

    Evidence Pharmacology, gene silencing, calcium imaging, patch clamp, knockout mice, and NFAT ChIP at the Nos2 promoter

    PMID:27246103

    Open questions at the time
    • Interaction with canonical NF-κB control not integrated
    • Restricted to microglial context
  17. 2017 High

    Defined a feed-forward NOS2/COX2 crosstalk loop in triple-negative breast cancer, with NO inducing COX2 via TRAF2 and PGE2 inducing NOS2.

    Evidence Enzyme inhibitors, TRAF2 assays, ER-stress analysis, and xenografts across two TNBC cell lines

    PMID:29087320

    Open questions at the time
    • Generalizability beyond TNBC cell lines unclear
    • Quantitative loop dynamics not modeled
  18. 2017 High

    Uncovered an epigenetic mechanism of NOS2 induction in which NLRC4/caspase-1-mediated PARP1 cleavage increases chromatin accessibility at NF-κB sites in the Nos2 promoter, placing caspase-1 downstream of NF-κB.

    Evidence Cytosolic flagellin stimulation, caspase-1 perturbation, PARP1 cleavage and chromatin accessibility assays with Salmonella infection

    PMID:28150715

    Open questions at the time
    • Direct demonstration that PARP1 cleavage product drives accessibility not fully isolated
    • Limited to inflammasome-activating contexts
  19. 2018 High

    Linked macrophage NOS2 to autoinflammatory disease by showing NOS2 drives IL-1α release and downstream IL-17 from innate lymphoid cells in psoriatic arthritis.

    Evidence Nos2 knockout mice and NOS inhibition in a mannan-induced PsA model corroborated by patient monocyte data

    PMID:29774240

    Open questions at the time
    • Mechanism connecting NO to IL-1α release not defined
    • Model-specific induction
  20. 2019 High

    Identified post-transcriptional restraint of NOS2 by showing tristetraprolin binds the Nos2 3'UTR to suppress epithelial expression, tuning colitis susceptibility.

    Evidence Epithelial-specific Zfp36 knockout mice, RNA-seq, 3'UTR binding assay, and DSS colitis model

    PMID:31595002

    Open questions at the time
    • Interplay with transcriptional induction not quantified
    • Restricted to intestinal epithelium
  21. 2020 High

    Defined the essential, non-redundant role of NOS2 in human anti-CMV immunity through a patient with inherited NO-null NOS2 deficiency and fatal CMV infection.

    Evidence Whole-exome sequencing and functional NO-production testing of a truncated mutant NOS2 allele

    PMID:31995689

    Open questions at the time
    • Single patient
    • Cellular mechanism by which NO controls CMV not defined
  22. 2020 Medium

    Demonstrated phagosomal NOS2 activation in microglia triggered by bacterial single-stranded RNA engaging TLR7, using real-time NO imaging.

    Evidence DNA-based ratiometric NO probes in live zebrafish brain phagosomes with TLR7 activation

    PMID:32554491

    Open questions at the time
    • Mechanistic coupling of TLR7 to phagosomal NOS2 not detailed
    • Single technically novel study
  23. 2022 High

    Connected NOS2 enzymatic output to immunometabolism by showing LACC1 converts the citrulline product to ornithine feeding ODC1-dependent polyamine metabolism in inflammatory macrophages.

    Evidence Reconstituted enzyme assay, multiple knockout mice (Lacc1, Nos2, Odc1), Salmonella infection, and ornithine chemical rescue

    PMID:35978195

    Open questions at the time
    • Flux contribution relative to other citrulline fates not quantified
    • Human in vivo relevance not addressed
  24. 2022 High

    Revealed an oncogenic epigenetic mechanism in which NOS2/NO drives DNMT1 degradation via p38-MAPK/KAT5, causing DNA hypomethylation, LINE-1 activation, and epithelial transformation.

    Evidence NOS2 overexpression, DNMT1 stability assays, p38/KAT5 manipulation, bisulfite sequencing, and LINE-1 readouts in human cell lines

    PMID:35584114

    Open questions at the time
    • In vivo tumorigenesis validation limited
    • Step linking NO to p38-MAPK activation not detailed
  25. 2023 High

    Established a metabolic-epigenetic axis controlling NOS2 mRNA stability, in which HIF-1α-recruited BRD4 supports glycolysis that stabilizes Nos2 mRNA for antibacterial NO production.

    Evidence Myeloid Brd4 conditional knockout mice, RNA-seq, BRD4 ChIP at glycolytic genes, glycolysis/NO assays, pyruvate rescue, and in vivo H. pylori infection

    PMID:37820788

    Open questions at the time
    • Direct RNA-stabilizing factor linking glycolysis to Nos2 mRNA not identified
    • Restricted to H. pylori macrophage context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many parallel transcriptional, post-transcriptional, metabolic, and post-translational inputs are quantitatively integrated to set NOS2 output in a given cell type, and how NO output is matched to specific effector outcomes, remains unresolved.
  • No unified quantitative model of NOS2 regulation across cell types
  • Cell-type-specific determinants of pro-survival vs cytotoxic vs oncogenic NO not defined
  • Structural and catalytic regulation of the human enzyme not addressed in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0016740 transferase activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CEBPBDNMT1LACC1PARP1RELASTAT1TRAF2ZFP36

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The human NOS2 gene is transcriptionally activated by cytokines (TNFα, IL-1β, IFNγ), with multiple cytokine-responsive regions identified in the 5' flanking region at -3.8 to -5.8 kb, -5.8 to -7.0 kb, and -7.0 to -16 kb upstream of the transcription start site; the first 3.8 kb upstream showed no cytokine-inducible activity, in contrast to the murine macrophage NOS2 promoter. Nuclear run-on analysis; luciferase reporter constructs transfected into human liver epithelial cells (AKN-1); deletion analysis of NOS2 5' flanking region Proceedings of the National Academy of Sciences of the United States of America High 8577713
2007 NOS2-derived NO S-nitrosylates NF-κB p65 at a conserved cysteine in the Rel homology domain, inhibiting NF-κB-dependent gene transcription; nuclear levels of S-nitrosylated p65 correlate with decreased p50-p65 heterodimer DNA binding and reduced NOS2 promoter occupancy, establishing a negative feedback loop whereby NOS2 limits its own expression. S-nitrosylation detection in cytokine-stimulated respiratory epithelial cells and macrophages; site-directed mutagenesis of p65 cysteine; NF-κB reporter assays; chromatin immunoprecipitation (ChIP) of NOS2 promoter The Journal of biological chemistry High 17720813
2022 LACC1 converts L-citrulline (the NOS2 reaction product) to L-ornithine and isocyanic acid, biochemically linking NOS2 to polyamine immunometabolism via ODC1; LACC1 phenotypes require upstream NOS2 and downstream ODC1 activity in inflammatory macrophages, demonstrated by genetic and chemical complementation. Biochemical enzyme assay; mouse genetic models (Lacc1-/-, Nos2-/-, Odc1 manipulation); bone marrow-derived macrophage infection with Salmonella; chemical complementation with L-ornithine Nature High 35978195
2022 NOS2 expression and associated NO signaling causes degradation of DNMT1 protein via an NO/p38-MAPK/KAT5-dependent mechanism, leading to global DNA hypomethylation, LINE-1 retrotransposon activation, and epithelial transformation in human cell lines. NOS2 overexpression in human cell lines; DNMT1 protein stability assays; p38-MAPK inhibition; KAT5 manipulation; bisulfite sequencing for methylation; LINE-1 expression and DNA damage assays Proceedings of the National Academy of Sciences of the United States of America High 35584114
2013 Induction and stability of human Th17 cells requires endogenous NOS2 activity within CD4+ T cells and the downstream canonical cGMP–cGK signaling pathway; NOS2 inhibition or cGMP-cGK blockade abolished de novo Th17 induction and selectively suppressed IL-17 production by established Th17 cells. NOS2 inhibition; cGMP-cGK pathway inhibition; differentiation of naive, memory, and tumor-infiltrating CD4+ T cells in vitro; cytokine measurement; patient-derived MDSCs and OvCa specimens The Journal of experimental medicine High 23797095
2016 In TLR4-activated microglia, Sur1-Trpm4 channels regulate Ca2+-sensitive calcineurin/NFAT signaling, which controls NOS2 transcription; inhibition or gene silencing of Sur1-Trpm4 reduces NFAT nuclear translocation and Nos2 upregulation, as confirmed by chromatin immunoprecipitation showing NFAT binding to the Nos2 promoter. Pharmacological inhibition of Sur1 (glibenclamide) and Trpm4 (9-phenanthrol); gene silencing of Abcc8 and Trpm4; calcium imaging; patch clamp; ChIP for NFAT at Nos2 promoter; qPCR; Griess assay for NO; primary microglia and N9 cell line; knockout mice (Abcc8-/-, Trpm4-/-) Journal of neuroinflammation High 27246103
2017 NO produced by NOS2 induces COX2 expression via TRAF2 activation (TNFα-dependent in MDA-MB-468 cells; TNFα-independent but ER-stress-dependent in MDA-MB-231 cells), while PGE2 (the COX2 product) induces NOS2 protein, establishing a feed-forward NOS2/COX2 crosstalk loop in triple-negative breast cancer cells. NOS2 and COX2 inhibition (aminoguanidine, aspirin/indomethacin); TRAF2 activity assays; TNFα neutralization; ER stress pathway analysis; xenograft tumor growth experiments; protein expression by Western blot Proceedings of the National Academy of Sciences of the United States of America High 29087320
2000 α-MSH inhibits LPS+IFNγ-induced NOS2 gene transcription in macrophages primarily by suppressing C/EBPβ (but not NF-κB) DNA-binding activity; deletion or mutation of the C/EBP box in the NOS2 promoter abolishes α-MSH's inhibitory effect, demonstrating that C/EBPβ is a required transcriptional activator of NOS2. Gel shift (EMSA) and supershift assays; NOS2 promoter-luciferase transfection with C/EBP box deletion/mutation constructs; RAW 264.7 macrophages Kidney international High 10844594
2017 Epigenetic regulation of Nos2 expression by the NLRC4 inflammasome requires caspase-1-mediated cleavage of PARP1 (ARTD1), which increases chromatin accessibility at NF-κB binding sites in the Nos2 promoter; caspase-1 acts downstream of NF-κB activation and is required for Nos2 transcription and NO-dependent macrophage resistance to Salmonella. Cytosolic flagellin stimulation; caspase-1 inhibition/knockout; NF-κB activation assays; PARP1 cleavage assays; chromatin accessibility assays; Salmonella infection of macrophages Scientific reports High 28150715
2002 Rho GTPase signaling through ROCK suppresses NOS2 production downstream of promoter activity, at the mRNA and protein level; statin-mediated HMG-CoA reductase inhibition increases cytokine-dependent NOS2 promoter activity via geranylgeranylation-dependent prenylation events independent of the Rho/ROCK pathway. ROCK inhibitor (Y-27632); statin treatment; geranylgeranyl pyrophosphate rescue; NOS2 promoter-luciferase assays; mRNA and protein level measurements in human alveolar epithelial cells American journal of physiology. Lung cellular and molecular physiology Medium 12169580
2001 An S714P missense mutation in NOS2 from Dahl/Rapp salt-sensitive rats reduces NOS2 protein half-life (demonstrated by metabolic labeling) without affecting steady-state mRNA levels, decreasing nitrite production in a manner dependent on L-arginine concentration; a proteasomal post-translational degradation mechanism is implicated. Transient transfection of wild-type, S714P, and S714A NOS2 mutants into COS-7 cells; metabolic labeling to measure protein half-life; immunoblot; nitrite production assay with varying L-arginine concentrations Circulation research High 11509447
1999 The pentanucleotide (CCTTT)n repeat within the NOS2A promoter functions as a transcriptional regulatory element; different repeat lengths confer different levels of IL-1β-inducible NOS2 promoter activity, with the 14-repeat allele showing the greatest induction in a luciferase reporter assay, and high-glucose conditions inhibit induction. Luciferase reporter gene assay with (CCTTT)n constructs of varying repeat length transfected into colonic carcinoma cells; IL-1β stimulation; high-glucose conditions FASEB journal Medium 10506586
2019 Tristetraprolin (TTP), encoded by Zfp36, directly binds AU-rich elements in the Nos2 3' UTR and suppresses Nos2 expression in intestinal epithelial cells; TTP knockout (Zfp36ΔIEC) mice show elevated Nos2 expression in the colonic epithelium and reduced susceptibility to DSS-induced colitis. Cre-lox conditional epithelial Zfp36 knockout mice; RNA-sequencing; TTP-Nos2 3'UTR interaction assay; DSS colitis model Scientific reports High 31595002
2023 BRD4 regulates glycolysis-dependent stabilization of Nos2 mRNA in macrophages upon H. pylori infection; BRD4 is recruited to promoters of glycolytic genes (Slc2a1, Hk2) via HIF-1α to support glycolysis, and BRD4-mediated glycolysis stabilizes Nos2 mRNA for NO production needed to kill H. pylori; Brd4-deficient macrophages show impaired glycolysis, reduced iNOS expression, and increased bacterial colonization. Brd4 myeloid-specific conditional knockout (Brd4-CKO) mice; RNA sequencing; ChIP of BRD4 at glycolytic gene promoters; glycolysis assays; NO/killing assays; pyruvate rescue; in vivo H. pylori infection model Cellular and molecular gastroenterology and hepatology High 37820788
2014 NOS2 expression and NO production in the tumor microenvironment is induced by hypoxia, serum withdrawal, IFNγ, and exogenous NO in ER-negative breast cancer cells, consistent with a feed-forward regulation; NOS2 inhibition suppresses markers of aggressive phenotype (S100A8, IL-6, IL-8, TIMP-1), reduces cellular migration, increases chemosensitivity to Taxol, and suppresses tumor xenograft growth and brain metastasis. NOS2 inhibition in MDA-MB-231 cells; stimulation with hypoxia, serum withdrawal, IFNγ, and NO donors; marker expression assays; migration assay; Taxol chemoresistance assay; nude mouse xenograft and fat-pad-to-brain metastasis model Proceedings of the National Academy of Sciences of the United States of America High 24733928
2018 Mannan-induced NOS2 expression in macrophages drives IL-1α release from skin macrophages, which promotes IL-17 production by innate lymphoid cells and psoriatic arthritis pathogenesis; genetic deletion or pharmacological inhibition of Nos2 suppresses disease, and NOS2 expression is upregulated in monocytes from PsA patients. Nos2 knockout mice in mannan-induced psoriasis/PsA model; NOS inhibitor (L-NAME); IL-1α measurement; innate lymphoid cell IL-17 assay; patient monocyte NOS2 expression Science advances High 29774240
2020 Inherited autosomal recessive NOS2 deficiency (homozygous frameshift mutation producing a truncated, NO-inactive NOS2 protein) in a human patient was associated with fatal CMV infection, establishing that NOS2 is required for control of CMV in humans; the patient was otherwise resistant to other common pathogens, suggesting NOS2 is redundant for control of most infections. Whole-exome sequencing; experimental testing of mutant NOS2 alleles for NO production; functional assays of truncated NOS2 protein The New England journal of medicine High 31995689
2015 NOS2-derived NO downregulates tight junction protein ZO-1 expression at the transcriptional level in human lung epithelial cells; NOS2-/- mice show attenuated inflammatory response to bleomycin-induced injury with reduced NF-κB DNA-binding activity and a shift toward alternative macrophage activation. NOS2 inhibitor 1400W via osmotic pump; NOS2-/- mice; bleomycin instillation model; NF-κB DNA-binding activity assay; BAL analysis; ZO-1 mRNA and protein measurement; macrophage activation markers Free radical biology & medicine Medium 26526764
2006 TLR4-mediated cardiomyocyte survival requires both MyD88 (the TLR4 adaptor) and NOS2; genetic deletion or pharmacological inhibition of NOS2 abolishes LPS-induced survival and functional rescue (Ca2+ transients, cell shortening) of cardiomyocytes under serum deprivation-induced apoptosis, placing NOS2 downstream of MyD88 in the TLR4 survival pathway. TLR4-/-, MyD88-/-, and pharmacological NOS2 inhibition in isolated cardiomyocytes; serum deprivation apoptosis model; TUNEL assay; DNA laddering; DNA-histone ELISA; Ca2+ transients; cell shortening measurements American journal of physiology. Heart and circulatory physiology High 16648192
1998 NOS2-derived NO mediates decreases in some cytochrome P450 catalytic activities (testosterone 6β-hydroxylase, 15α- and 16β-hydroxylase) during endotoxemia, as demonstrated by absence of these activity decreases in NOS2 knockout mice or aminoguanidine-treated mice; however, LPS-induced decreases in CYP2C29, CYP3A11 mRNA and CYP2E1, CYP2C-like, CYP3A-like protein levels occur independently of NOS2/NO. NOS2 knockout mice; aminoguanidine NOS inhibitor; LPS-induced endotoxemia model; cytochrome P450 mRNA and protein expression; testosterone hydroxylase activity assays Molecular pharmacology High 9687568
2010 NOD1 (but not TLR4) is the dominant pathway for NOS2 induction in vascular smooth muscle cells; NOD1-mediated NOS2 induction requires Rip2 kinase (inhibited by PP2) whereas TLR4-mediated macrophage NOS2 induction requires caspase activity and PKC; both pathways converge on NF-κB and MAPK signaling. Pharmacological inhibitors (SC-514 for NF-κB, SB203580/PD98059 for MAPK, z-VAD-fmk for caspase, Gö6976 for PKC, PP2 for Rip2); NOD1 agonist FK565; LPS for TLR4; NOS2 protein expression and NO production in vascular smooth muscle cells vs. macrophages British journal of pharmacology Medium 20649597
2015 IL-17 intensifies IFNγ-induced NOS2 upregulation in RAW 264.7 macrophages by further activating STAT1 phosphorylation (Y701) and NF-κB nuclear translocation; IL-17 enhances p38 MAPK phosphorylation and limits ERK1/2 phosphorylation, thereby augmenting NF-κB pathway activity and NOS2 transcription. ChIP confirmed enhanced STAT1 and NF-κB binding to the NOS2 promoter. Western blot for STAT1, NF-κB, p38 MAPK, ERK1/2 phosphorylation; ChIP assay for STAT1 and NF-κB at NOS2 promoter; STAT1 and NF-κB inhibitors; colorimetric NO assay; qPCR International journal of molecular medicine Medium 26677135
2004 Manganese potentiates LPS-induced NOS2 expression in C6 glioma cells through mitochondrial ROS production, which activates NF-κB (via NIK-mediated IκBα phosphorylation); overexpression of dominant-negative IκBα or NIK mutant, or scavenging mitochondrial ROS with MitoQ, attenuates Mn-enhanced NOS2 expression. Overexpression of mutant IκBα (S32/36A) and dominant-negative NIK; MitoQ mitochondrial antioxidant; gel shift for NF-κB p65/p50; mitochondrial membrane potential and calcium assays; ROS measurement; NOS2 protein and NO assays Brain research. Molecular brain research Medium 15010209
2020 DNA-based probes targeting phagosomal NO demonstrate that single-stranded RNA of bacterial origin acts as a PAMP that activates NOS2 in microglia phagosomes by engaging TLR-7; this PAMP-TLR7 interaction triggers rapid phagosomal NOS2 activity, mapped in live zebrafish brains. DNA-based ratiometric NO probes delivered to phagosomes and endosomes; live zebrafish brain imaging; TLR-7 activation; microglia phagosomal NO measurement Proceedings of the National Academy of Sciences of the United States of America Medium 32554491
2014 NOS2 expression is restricted to scattered neurons in specific brain regions (piriform and entorhinal cortex, amygdala, thalamus, hypothalamus, dentate gyrus, cerebellum) in the healthy brain, but inflammation (intracerebral LPS + IFNγ) triggers transient NOS2 expression in microglia rather than neurons; NOS2 expression is rarely detected in microglia under non-inflammatory conditions. Transgenic mouse expressing tdTomato and CRE recombinase under Nos2 regulatory regions (lineage tracing); immunohistochemistry; intracerebral LPS + IFNγ injection Glia High 24615726
2004 NOS2 promotes apoptosis in acute cardiac allograft rejection via p53-dependent mechanisms; NOS2-deficient recipients show reduced p53 transcript levels, increased Bcl-2/Bax ratio, decreased Bcl-Xl, lower caspase-1 and -3 activity, and fewer TUNEL-positive nuclei; Fas/FasL and TNFα/TNFR1 pathways are not altered by NOS2 deficiency. NOS2 knockout recipient mice in heterotopic cardiac transplant model; TUNEL assay; antinucleosome ELISA; 32P-RT-PCR for caspase-1/-3, p53, Bcl-2, Bax, Bcl-Xl; DEVD-pNA caspase-3 activity; PARP cleavage Circulation High 9989972

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proceedings of the National Academy of Sciences of the United States of America 347 8577713
1999 nos-1 and nos-2, two genes related to Drosophila nanos, regulate primordial germ cell development and survival in Caenorhabditis elegans. Development (Cambridge, England) 278 10518502
2007 NOS2 regulation of NF-kappaB by S-nitrosylation of p65. The Journal of biological chemistry 195 17720813
2014 Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America 146 24733928
1999 Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 134 10593859
2009 NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. The Journal of neuroscience : the official journal of the Society for Neuroscience 121 19906966
1999 Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 121 10506586
1999 Expression of cardiac cytokines and inducible form of nitric oxide synthase (NOS2) in Trypanosoma cruzi-infected mice. Journal of molecular and cellular cardiology 111 10072717
2015 Signaling and stress: The redox landscape in NOS2 biology. Free radical biology & medicine 105 26117324
2013 Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. The Journal of experimental medicine 98 23797095
2003 Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice. American journal of physiology. Lung cellular and molecular physiology 91 12972406
2017 Coexpression of NOS2 and COX2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America 88 29087320
2008 The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. Journal of Alzheimer's disease : JAD 84 19096157
2018 PM2.5 induces autophagy-mediated cell death via NOS2 signaling in human bronchial epithelium cells. International journal of biological sciences 76 29805307
2017 Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism. Scientific reports 75 28276497
2006 Translational repression restricts expression of the C. elegans Nanos homolog NOS-2 to the embryonic germline. Developmental biology 74 16499902
1999 Attenuated acute cardiac rejection in NOS2 -/- recipients correlates with reduced apoptosis. Circulation 74 9989972
1998 Down-regulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene. Molecular pharmacology 74 9687568
2016 Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression. The American journal of pathology 73 26806087
2016 The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. Journal of neuroinflammation 72 27246103
2009 NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans. Human genetics 69 19575238
2017 NOS2 as an Emergent Player in Progression of Cancer. Antioxidants & redox signaling 68 28506076
2006 MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. American journal of physiology. Heart and circulatory physiology 62 16648192
2009 Comparative analysis of zebrafish nos2a and nos2b genes. Gene 60 19501636
2004 Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB. Brain research. Molecular brain research 59 15010209
2022 LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature 56 35978195
2012 NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression. International journal of cancer 56 22618808
2004 Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis. Annals of neurology 52 15174013
2003 Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria. Human genetics 51 12552317
2002 Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells. American journal of physiology. Lung cellular and molecular physiology 45 12169580
2000 Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease. Nitric oxide : biology and chemistry 45 10944422
1998 NOS2 mediates opposing effects in models of acute and chronic cardiac rejection: insights from NOS2-knockout mice. The American journal of pathology 45 9811327
2007 Influence of the inducible nitric oxide synthase gene (NOS2A) on inflammatory bowel disease susceptibility. Immunogenetics 44 17955236
2002 Pattern of NOS2 and NOS3 mRNA expression in human A549 cells and primary cultured AEC II. American journal of physiology. Lung cellular and molecular physiology 43 11880293
2007 Inhibition of spinal constitutive NOS-2 by 1400W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation. The European journal of neuroscience 41 17561811
2020 Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency. The New England journal of medicine 40 31995689
2014 NOS2 expression is restricted to neurons in the healthy brain but is triggered in microglia upon inflammation. Glia 40 24615726
2008 Novel noncoding antisense RNA transcribed from human anti-NOS2A locus is differentially regulated during neuronal differentiation of embryonic stem cells. RNA (New York, N.Y.) 40 18820242
2003 Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations. Genes and immunity 40 14551604
2012 NOS-2 signaling and cancer therapy. IUBMB life 39 22715033
2018 Mannan-induced Nos2 in macrophages enhances IL-17-driven psoriatic arthritis by innate lymphocytes. Science advances 38 29774240
2018 Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation. International journal of molecular sciences 38 30227679
2009 Association of SLC11A1 with tuberculosis and interactions with NOS2A and TLR2 in African-Americans and Caucasians. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 38 19723394
2004 Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats. Ocular immunology and inflammation 38 15512981
2001 (CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy. The Journal of allergy and clinical immunology 38 11692109
2008 Peripheral antinociceptive effects of mu- and delta-opioid receptor agonists in NOS2 and NOS1 knockout mice during chronic inflammatory pain. European journal of pharmacology 37 19041302
2018 Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective. British journal of pharmacology 36 30152521
2013 Zinc ferrite nanoparticles activate IL-1b, NFKB1, CCL21 and NOS2 signaling to induce mitochondrial dependent intrinsic apoptotic pathway in WISH cells. Toxicology and applied pharmacology 36 24035972
2017 NOS2 expression in glioma cell lines and glioma primary cell cultures: correlation with neurosphere generation and SOX-2 expression. Oncotarget 35 28424427
2015 Role of NOS2 in pulmonary injury and repair in response to bleomycin. Free radical biology & medicine 35 26526764
2012 Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA--a simultaneous study of 130 potentially functional SNPs in 14 candidate genes. Rheumatology (Oxford, England) 35 22258388
2006 Effects of noradrenaline on neuronal NOS2 expression and viability. Antioxidants & redox signaling 34 16771678
2020 MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2. PLoS pathogens 33 31999809
2020 DNA-based fluorescent probes of NOS2 activity in live brains. Proceedings of the National Academy of Sciences of the United States of America 33 32554491
1995 Three members of the nitric oxide synthase II gene family (NOS2A, NOS2B, and NOS2C) colocalize to human chromosome 17. Genomics 33 7558036
2019 NOS2 inhibitor 1400W Induces Autophagic Flux and Influences Extracellular Vesicle Profile in Human Glioblastoma U87MG Cell Line. International journal of molecular sciences 32 31226744
2006 NOS2A and the modulating effect of cigarette smoking in Parkinson's disease. Annals of neurology 31 16823855
2019 Melatonin and Leishmania amazonensis Infection Altered miR-294, miR-30e, and miR-302d Impacting on Tnf, Mcp-1, and Nos2 Expression. Frontiers in cellular and infection microbiology 30 30949455
2006 Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist. Antioxidants & redox signaling 30 16771677
2016 Association of NOS2 and NOS3 gene polymorphisms with susceptibility to type 2 diabetes mellitus and diabetic nephropathy in the Chinese Han population. IUBMB life 28 27192959
2014 mNos2 deletion and human NOS2 replacement in Alzheimer disease models. Journal of neuropathology and experimental neurology 28 25003233
2006 Association analysis of common variants of ELN, NOS2A, APOE and ACE2 to intracranial aneurysm. Stroke 28 16574921
2004 PGE1-induced NO reduces apoptosis by D-galactosamine through attenuation of NF-kappaB and NOS-2 expression in rat hepatocytes. Hepatology (Baltimore, Md.) 28 15565661
2020 Heme oxygenase-1 inhibition promotes IFNγ- and NOS2-mediated control of Mycobacterium tuberculosis infection. Mucosal immunology 27 32862202
2011 Gene deletion of nos2 protects against manganese-induced neurological dysfunction in juvenile mice. Toxicological sciences : an official journal of the Society of Toxicology 27 22174044
2017 Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage. Scientific reports 26 28150715
2017 High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex. Translational psychiatry 26 28244985
2022 NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression. Proceedings of the National Academy of Sciences of the United States of America 25 35584114
2015 NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury. Toxicological sciences : an official journal of the Society of Toxicology 25 25870319
2016 Macrophage NOS2 in Tumor Leukocytes. Antioxidants & redox signaling 24 27397579
2022 The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel, Switzerland) 23 35740092
2012 Single nucleotide polymorphisms in the NOS2 and NOS3 genes are associated with exhaled nitric oxide. Journal of medical genetics 23 22368302
2000 alpha-MSH inhibits induction of C/EBPbeta-DNA binding activity and NOS2 gene transcription in macrophages. Kidney international 23 10844594
2010 Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages. British journal of pharmacology 21 20649597
2000 The CCTTT polymorphism in the NOS2A gene is associated with dementia with Lewy bodies. Neuroreport 21 10674474
2024 NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer. International journal of molecular sciences 20 38892290
2023 BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection. Cellular and molecular gastroenterology and hepatology 20 37820788
2022 Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density. Redox biology 20 36375380
2009 Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Human genetics 20 19859740
2006 Characterization of NO and cytokine production in immune-activated microglia and peritoneal macrophages derived from a mouse model expressing the human NOS2 gene on a mouse NOS2 knockout background. Antioxidants & redox signaling 20 16771679
2004 Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice. Journal of hepatology 20 15158332
2001 Nitric oxide synthase (NOS2) mutation in Dahl/Rapp rats decreases enzyme stability. Circulation research 20 11509447
2008 (CCTTT)n polymorphism of NOS2A in nasal polyposis and asthma: a case-control study. Journal of investigational allergology & clinical immunology 19 18714530
2003 Effect of NOS2 gene deficiency on the development of autoantibody mediated arthritis and subsequent articular cartilage degeneration. The Journal of rheumatology 19 12563676
2019 Tristetraprolin targets Nos2 expression in the colonic epithelium. Scientific reports 18 31595002
1999 Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration. Hepatology (Baltimore, Md.) 18 10462376
2019 Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition. Scientific reports 16 31015500
2015 IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB. International journal of molecular medicine 16 26677135
2014 NOS2 is critical to the development of emphysema in Sftpd deficient mice but does not affect surfactant homeostasis. PloS one 16 24465666
2013 Association analysis of nitric oxide synthases: NOS1, NOS2A and NOS3 genes, with multiple sclerosis. Annals of human biology 16 23826716
2010 Analysis of single nucleotide polymorphisms in the NOS2A gene and interaction with smoking in age-related macular degeneration. Annals of human genetics 16 20374233
2006 Lack of association between NOS2 pentanucleotide repeat polymorphism and asthma phenotypes or exhaled nitric oxide concentration. Pediatric pulmonology 16 16703578
2016 Analysis of polymorphisms in Interleukin 10, NOS2A, and ESR2 genes in chronic and aggressive periodontitis. Brazilian oral research 15 27737359
2015 The role of NOS2A -954G/C and vascular endothelial growth factor +936C/T polymorphisms in type 2 diabetes mellitus and diabetic nonproliferative retinopathy risk management. Therapeutics and clinical risk management 15 26664124
2004 Inducible nitric oxide synthase gene (NOS2A) haplotypes and the outcome of hepatitis C virus infection. Genes and immunity 15 14985675
2023 Interferon-gamma is quintessential for NOS2 and COX2 expression in ER- breast tumors that lead to poor outcome. Cell death & disease 14 37169743
2003 No association of inducible nitric oxide synthase gene ( NOS2A) to multiple sclerosis. Journal of neurology 14 12736741
2022 Jatrorrhizine alleviates ulcerative colitis via regulating gut microbiota and NOS2 expression. Gut pathogens 13 36271438
2018 Propolis modulates NOS2/arginase-1 pathway in tropomyosin-induced experimental autoimmune uveitis. Inflammopharmacology 13 29752572
2009 NO role of NOS2A susceptibility polymorphisms in rheumatoid arthritis. Nitric oxide : biology and chemistry 13 19635578

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