Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy

Hibbs, J B; Westenfelder, C; Taintor, R; Vavrin, Z; Kablitz, C; Baranowski, R L; Ward, J H; Menlove, R L; McMurry, M P; Kushner, J P

doi:10.1172/jci115666

Cited by 485Nitric Oxide and Endothelin EffectsImmune cells in cancerAngiogenesis and VEGF in Cancer

Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy

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Hibbs, J B, Westenfelder, C, Taintor, R, Vavrin, Z, Kablitz, C, Baranowski, R L, Ward, J H, Menlove, R L +2 more·1992·Journal of Clinical Investigation

DOI 10.1172/jci115666PMC PMC442932

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Abstract

An interferon-gamma, tumor necrosis factor, and interleukin-1-inducible, high-output pathway synthesizing nitric oxide (NO) from L-arginine was recently identified in rodents. High-dose interleukin-2 (IL-2) therapy is known to induce the same cytokines in patients with advanced cancer. Therefore, we examined renal cell carcinoma (RCC; n = 5) and malignant melanoma (MM; n = 7) patients for evidence of cytokine-inducible NO synthesis. Activity of this pathway was evaluated by measuring serum and urine nitrate (the stable degradation product of NO) during IL-2 therapy. IL-2 administration caused a striking increase in NO generation as reflected by serum nitrate levels (10- and 8-fold increase [P less than 0.001, P less than 0.003] for RCC and MM patients, respectively) and 24-h urinary nitrate excretion (6.5- and 9-fold increase [both P less than 0.001] for RCC and MM patients, respectively). IL-2-induced renal dysfunction made only a minor contribution to increased serum nitrate levels. Metabolic tracer studies using L-[guanidino-15N2]arginine demonstrated that the increased nitrate production was derived from a terminal guanidino nitrogen atom of L-arginine. Our results showing increased endogenous nitrate synthesis in patients receiving IL-2 demonstrate for the first time that a cytokine-inducible, high-output L-arginine/NO pathway exists in humans.

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During inflammatory reactions or infection involving increased iNOS expression, large amounts of NO are produced resulting in significant increases in plasma nitrate and nitrite.
“Importantly, during inflammatory reactions or infection involving increased iNOS expression large amounts of NO are produced resulting in significant increases in plasma nitrate and nitrite [42–44].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [43]

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Nitric oxide as a secretory product of mammalian cells
Nathan, C. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.12.1381691 · Cited by 4,350 · see citing works
Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity.
Fang, F. C. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119473 · Cited by 1,139 · see citing works
Extensive Nitration of Protein Tyrosines in Human Atherosclerosis Detected by Immunohistochemistry
Beckman, J. S., Ye, Y. Z., Anderson, P. G., Chen, J., Accavitti, M. A., Tarpey, M. M., & White, C. R. (1994) · Biological Chemistry Hoppe-Seyler · doi:10.1515/bchm3.1994.375.2.81 · Cited by 1,122 · see citing works
Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
Förstermann, U., Closs, E. I., Pollock, J. S., Nakane, M., Schwarz, P., Gath, I., & Kleinert, H. (1994) · Hypertension · doi:10.1161/01.hyp.23.6.1121 · Cited by 1,115 · see citing works
Analysis of nitrite and nitrate in biological fluids by assays based on the Griess reaction: Appraisal of the Griess reaction in the l-arginine/nitric oxide area of research
Tsikas, D. (2006) · Journal of Chromatography B · doi:10.1016/j.jchromb.2006.07.054 · Cited by 897 · see citing works
Inflammation, immunoregulation, and inducible nitric oxide synthase
Nussler, A. K., & Billiar, T. R. (1993) · Journal of Leukocyte Biology · doi:10.1002/jlb.54.2.171 · Cited by 859 · see citing works
Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes.
Geller, D. A., Lowenstein, C. J., Shapiro, R. A., Nussler, A. K., Silvio, M. D., Wang, S. C., Nakayama, D. K., Simmons, R. L., Snyder, S. H., & Billiar, T. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3491 · Cited by 821 · see citing works
Molecular mechanisms and therapeutic strategies related to nitric oxide
Moncada, S., & Higgs, E. A. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.13.7557022 · Cited by 776 · see citing works
Nitric oxide and redox mechanisms in the immune response
Wink, D. A., Hines, H. B., Cheng, R. Y. S., Switzer, C. H., Flores-Santana, W., Vitek, M. P., Ridnour, L. A., & Colton, C. A. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.1010550 · Cited by 765 · see citing works
Nitrate, bacteria and human health
Lundberg, J. O., Weitzberg, E., Cole, J. A., & Benjamin, N. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro929 · Cited by 739 · see citing works
Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases
Lucey, D. R., Clerici, M., & Shearer, G. M. (1996) · Clinical Microbiology Reviews · doi:10.1128/cmr.9.4.532 · Cited by 664 · see citing works
INHIBITION OF NITRIC OXIDE SYNTHASE AS A POTENTIAL THERAPEUTIC TARGET
Hobbs, A. J., Higgs, A., & Moncada, S. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.191 · Cited by 596 · see citing works
Quantitation of nitrate and nitrite in extracellular fluids
Grisham, M. B., Johnson, G. G., & Lancaster, J. R. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)68026-4 · Cited by 542 · see citing works
Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction
Granger, D. L., Taintor, R. R., Boockvar, K. S., & Hibbs, J. B. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)68016-1 · Cited by 511 · see citing works
Expression of Inducible Nitric Oxide Synthase in Human Heart Failure
Haywood, G. A., Tsao, P. S., von der Leyen, H. E., Mann, M. J., Keeling, P. J., Trindade, P. T., Lewis, N. P., Byrne, C. D., Rickenbacher, P. R., Bishopric, N. H., et al. (1996) · Circulation · doi:10.1161/01.cir.93.6.1087 · Cited by 490 · see citing works
Free radicals and phagocytic cells
Rosen, G. M., Pou, S., Ramos, C. L., Cohen, M. S., & Britigan, B. E. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.2.7540156 · Cited by 478 · see citing works
In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases.
Koprowski, H., Zheng, Y., Heber‐Katz, E., Fraser, N., RORKE, L. B., Fu, Z. F., Hanlon, C. A., & Dietzschold, B. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.3024 · Cited by 474 · see citing works
Nitric oxide in septic shock
Titheradge, M. A. (1999) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(99)00031-6 · Cited by 457 · see citing works
Mechanisms of nitric oxide-related antimicrobial activity
Fang, F. C. (1997) · Journal of Clinical Investigation · Cited by 446 · see citing works
Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages
Weinberg, J., Misukonis, M., Shami, P., Mason, S. N., Sauls, D., Dittman, W. A., Wood, E., Smith, G., McDonald, B., & Bachus, K. (1995) · Blood · doi:10.1182/blood.v86.3.1184.1184 · Cited by 435 · see citing works
Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis
Natanson, C., Hoffman, W. D., Suffredini, A. F., Eichacker, P. Q., & Danner, R. L. (1994) · Annals of Internal Medicine · doi:10.7326/0003-4819-120-9-199405010-00009 · Cited by 440 · see citing works
Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression.
Anstey, N. M., Weinberg, J. B., Hassanali, M. Y., Mwaikambo, E. D., Manyenga, D., Misukonis, M. A., Arnelle, D. R., Hollis, D. R., McDonald, M., & Granger, D. L. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.2.557 · Cited by 431 · see citing works
Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans.
Corbett, J. A., Sweetland, M. A., Wang, J., Lancaster, J. R., & McDaniel, M. L. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1731 · Cited by 411 · see citing works
Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene.
Chartrain, N. A., Geller, D. A., Koty, P. P., Sitrin, N. F., Nussler, A. K., Hoffman, E. P., Billiar, T. R., Hutchinson, N. I., & Mudgett, J. S. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37441-0 · Cited by 394 · see citing works
The role of nitric oxide in the pathogenesis of preeclampsia
Seligman, S. P., Buyon, J. P., Clancy, R. M., Young, B. K., & Abramson, S. B. (1994) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(94)70064-8 · Cited by 379 · see citing works
Basal nitric oxide synthesis in essential hypertension
Forte, P., Copland, M., Smith, L. M., Milne, E., Sutherland, J., & Benjamin, N. (1997) · The Lancet · doi:10.1016/s0140-6736(96)07631-3 · Cited by 372 · see citing works
Role of nitric oxide in parasitic infections
James, S. L. (1995) · Microbiological Reviews · doi:10.1128/mr.59.4.533-547.1995 · Cited by 357 · see citing works
NO Inhibitions: Antimicrobial Properties of Nitric Oxide
Groote, M. A. D., & Fang, F. C. (1995) · Clinical Infectious Diseases · doi:10.1093/clinids/21.supplement_2.s162 · Cited by 353 · see citing works
ReviewMethods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids
Tsikas, D. (2005) · Free Radical Research · doi:10.1080/10715760500053651 · Cited by 357 · see citing works
Nitric Oxide in the Vasculature: Physiology and Pathophysiology
Moncada, S. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb51989.x · Cited by 340 · see citing works
Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease.
DINERMAN, J. L., Lowenstein, C. J., & Snyder, S. H. (1993) · Circulation Research · doi:10.1161/01.res.73.2.217 · Cited by 336 · see citing works
Molecular biology of nitric oxide synthases
Geller, D. A., & Billiar, T. R. (1998) · Cancer and Metastasis Reviews · doi:10.1023/a:1005940202801 · Cited by 333 · see citing works
Nitric Oxide Synthase Is Not a Constituent of the Antimicrobial Armature of Human Mononuclear Phagocytes
Schneemann, M., Schoedon, G., Hofer, S., Blau, N., Guerrero, L., & Schaffner, A. (1993) · The Journal of Infectious Diseases · doi:10.1093/infdis/167.6.1358 · Cited by 333 · see citing works
Improved Methods to Measure End Products of Nitric Oxide in Biological Fluids: Nitrite, Nitrate, andS-Nitrosothiols
Marzinzig, M., Nussler, A. K., Stadler, J., Marzinzig, E., Barthlen, W., Nüssler, N. C., Beger, H. G., Morris, S. M., & Brückner, U. B. (1997) · Nitric Oxide · doi:10.1006/niox.1997.0116 · Cited by 331 · see citing works
Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas.
Garvey, E. P., Oplinger, J. A., Tanoury, G. J., Sherman, P. A., Fowler, M., Marshall, S., Harmon, M. F., Paith, J. E., & Furfine, E. S. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47071-8 · Cited by 316 · see citing works
Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis.
Shultz, P. J., & Raij, L. R. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116045 · Cited by 310 · see citing works
Nitrate determination in biological fluids by an enzymatic one-step assay with nitrate reductase
Bories, P.-N., & Bories, C. (1995) · Clinical Chemistry · doi:10.1093/clinchem/41.6.904 · Cited by 304 · see citing works
Genetic Contribution of the Endothelial Constitutive Nitric Oxide Synthase Gene to Plasma Nitric Oxide Levels
Wang, X. L., Mahaney, M. C., Sim, A. S., Wang, J., Wang, J., Blangero, J., Almasy, L. A., Badenhop, R. B., & Wilcken, D. E. L. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.11.3147 · Cited by 291 · see citing works
Role of nitric oxide in tumour progression: Lessons from human tumours
Thomsen, L. L., & Miles, D. W. (1998) · Cancer and Metastasis Reviews · doi:10.1023/a:1005912906436 · Cited by 276 · see citing works
Human monocytes/macrophages: NO or no NO?
Denis, M. (1994) · Journal of Leukocyte Biology · doi:10.1002/jlb.55.5.682 · Cited by 274 · see citing works
Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome
Paul, B. D., Lemle, M. D., Komaroff, A. L., & Snyder, S. H. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2024358118 · Cited by 271 · see citing works
Overproduction of Nitric Oxide in Cytokine-Mediated and Septic Shock
Kilbourn, R. G., & Griffith, O. W. (1992) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/84.11.827 · Cited by 268 · see citing works
The Emerging Multifaceted Roles of Nitric Oxide
Kuo, P. C., & Schroeder, R. A. (1995) · Annals of Surgery · doi:10.1097/00000658-199503000-00003 · Cited by 266 · see citing works
Circulating Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted With 17β-Estradiol and Norethisterone Acetate
Rosselli, M., Imthurn, B., Keller, P. J., Jackson, E. K., & Dubey, R. K. (1995) · Hypertension · doi:10.1161/01.hyp.25.4.848 · Cited by 264 · see citing works
Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP.
Werner-Felmayer, G., Werner, E. R., Fuchs, D., Hausen, A., Reibnegger, G., Schmidt, K., Weiss, G., & Wachter, H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53931-4 · Cited by 263 · see citing works
Glomerular actions of nitric oxide
Raij, L. R., & Baylis, C. (1995) · Kidney International · doi:10.1038/ki.1995.262 · Cited by 262 · see citing works
Methylene blue administration in septic shock
Preiser, J., Lejeune, P., Roman, A., Carlier, E., Backer, D. D., Leeman, M., Kahn, R. J., & Vincent, J. (1995) · Critical Care Medicine · doi:10.1097/00003246-199502000-00010 · Cited by 262 · see citing works
Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide.
Shultz, P. J., & Tolins, J. P. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116244 · Cited by 254 · see citing works
Platelet-Endothelium Interactions
Flier, J. S., Underhill, L. H., Ware, J. A., & Heistad, D. D. (1993) · New England Journal of Medicine · doi:10.1056/nejm199303043280907 · Cited by 250 · see citing works
The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta.
Pinsky, D. J., Cai, B., Yang, X., Rodriguez, C., Sciacca, R. R., & Cannon, P. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117713 · Cited by 248 · see citing works
Arginine de novo and nitric oxide production in disease states
Luiking, Y. C., Have, G. A. M. T., Wolfe, R. R., & Deutz, N. E. P. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00284.2012 · Cited by 243 · see citing works
Nitric oxide in inflammation and immune response
Moilanen, E., & Vapaatalo, H. (1995) · Annals of Medicine · doi:10.3109/07853899509002589 · Cited by 242 · see citing works
The role of nitric oxide in cardiac depression induced by interleukin‐1β and tumour necrosis factor‐α
Schulz, R., Panas, D. L., Catena, R., Moncada, S., Olley, P. M., & Lopaschuk, G. D. (1995) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1995.tb14901.x · Cited by 228 · see citing works
Endotoxin triggers the expression of an inducible isoform of nitric oxide synthase and the formation of peroxynitrite in the rat aorta in vivo
Szabó, C., Salzman, A. L., & Ischiropoulos, H. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00322-z · Cited by 228 · see citing works
Erythropoietin stimulates proliferation of human renal carcinoma cells
Westenfelder, C. S., & Baranowski, R. L. (2000) · Kidney International · doi:10.1046/j.1523-1755.2000.00211.x · Cited by 222 · see citing works
The Role of the l-arginine: Nitric Oxide Pathway in Circulatory Shock
Thiemermann, C. (1994) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60493-7 · Cited by 220 · see citing works
Tumor necrosis factor α: A major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats
López-Talavera, J. C., Merrill, W. W., & Groszmann, R. J. (1995) · Gastroenterology · doi:10.1016/0016-5085(95)90449-2 · Cited by 219 · see citing works
Macrophage Arginine Metabolism to Ornithine/Urea or Nitric Oxide/Citrulline: A Life or Death Issue
Mills, C. D. (2001) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v21.i5.10 · Cited by 212 · see citing works
Interleukin-2 as a neuroregulatory cytokine
Hanisch, U., & Quirion, R. (1995) · Brain Research Reviews · doi:10.1016/0165-0173(95)00015-1 · Cited by 211 · see citing works
Measurement of nitrite and nitrate levels in plasma and urine — what does this measure tell us about the activity of the endogenous nitric oxite system?
Baylis, C., & Vallance, P. J. (1998) · Current Opinion in Nephrology & Hypertension · doi:10.1097/00041552-199801000-00010 · Cited by 210 · see citing works
Arginine and Citrulline and the Immune Response in Sepsis
Wijnands, K. A. P., Castermans, T. M. R., Hommen, M., Meesters, D. M., & Poeze, M. (2015) · Nutrients · doi:10.3390/nu7031426 · Cited by 208 · see citing works
The arginine‐nitric oxide pathway: A target for new drugs
Kerwin, J. F., & Heller, M. (1994) · Medicinal Research Reviews · doi:10.1002/med.2610140103 · Cited by 204 · see citing works
Role of nitric oxide synthesis in salt-sensitive hypertension in Dahl/Rapp rats.
Chen, P. Y., & Sanders, P. W. (1993) · Hypertension · doi:10.1161/01.hyp.22.6.812 · Cited by 201 · see citing works
Nitric Oxide Production and Nitric Oxide Synthase Type 2 Expression by Human Mononuclear Phagocytes: A Review
Weinberg, J. B. (1998) · Molecular Medicine · doi:10.1007/bf03401758 · Cited by 193 · see citing works
Comparison of the roles of reactive oxygen and nitrogen intermediates in the host response to Mycobacterium tuberculosis using transgenic mice
Adams, L. B., Dinauer, M. C., Morgenstern, D. E., & Krahenbuhl, J. L. (1997) · Tubercle and Lung Disease · doi:10.1016/s0962-8479(97)90004-6 · Cited by 184 · see citing works
Nitric Oxide Synthases: Gene Structure and Regulation
Wang, Y., & Marsden, P. A. (1995) · Advances in pharmacology · doi:10.1016/s1054-3589(08)61081-9 · Cited by 187 · see citing works
Interleukin-2
Whittington, R., & Faulds, D. M. (1993) · Drugs · doi:10.2165/00003495-199346030-00009 · Cited by 179 · see citing works
Spin trapping of nitric oxide produced in vivo in septic‐shock mice
Lai, C., & Komarov, A. M. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00422-6 · Cited by 175 · see citing works
Nitric Oxide Is Generated on the Skin Surface by Reduction of Sweat Nitrate
Weller, R., Pattullo, S., Smith, L. M., Golden, M., Ormerod, A. D., & Benjamin, N. (1996) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12363167 · Cited by 172 · see citing works
Free Radical Chemistry of Nitric Oxide
Freeman, B. Α. (1994) · CHEST Journal · doi:10.1378/chest.105.3_supplement.79s · Cited by 167 · see citing works
The Role of Nitric Oxide in Inflammation
Lyons, C. R. (1995) · Advances in immunology · doi:10.1016/s0065-2776(08)60589-1 · Cited by 169 · see citing works
The Physiological and Pathological Chemistry of Nitric Oxide
Beckman, J. S. (1996) · Elsevier eBooks · doi:10.1016/b978-012435555-2/50002-4 · Cited by 168 · see citing works
Arginine-Supplemented Diets Improve Survival in Gut-Derived Sepsis and Peritonitis by Modulating Bacterial Clearance The Role of Nitric Oxide
Gianotti, L. V., Alexander, J., Pyles, T., & Fukushima, R. (1993) · Annals of Surgery · doi:10.1097/00000658-199306000-00006 · Cited by 167 · see citing works
[6] Measuring nitric oxide production in human clinical studies
Granger, D. L., Anstey, N. M., Miller, W. C., & Weinberg, J. B. (1999) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(99)01068-x · Cited by 159 · see citing works
Nitric oxide and septic shock.
Cobb, J. P., & Danner, R. L. (1996) · PubMed · Cited by 156 · see citing works
The pathophysiology of canine babesiosis: new approaches to an old puzzle.
Jacobson, L. S., & Clark, I. A. (1994) · PubMed · Cited by 156 · see citing works
Decreased Activity of the l -Arginine–Nitric Oxide Metabolic Pathway in Patients With Congestive Heart Failure
Katz, S. D., Khan, T., Zeballos, G. A., Mathew, L., Potharlanka, P., Knecht, M., & Whelan, J. (1999) · Circulation · doi:10.1161/01.cir.99.16.2113 · Cited by 153 · see citing works
Is nitric oxide overproduction the target of choice for the management of septic shock?
Feihl, F., Waeber, B., & Liaudet, L. (2001) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(01)00155-3 · Cited by 151 · see citing works
Nitric Oxide and Parasitic Disease
Clark, I. A., & Rockett, K. A. (1996) · Advances in Parasitology/Advances in parasitology · doi:10.1016/s0065-308x(08)60218-3 · Cited by 151 · see citing works
Induction of Nitric Oxide Synthase in the Human Cardiac Allograft Is Associated With Contractile Dysfunction of the Left Ventricle
Lewis, N. P., Tsao, P. S., Rickenbacher, P. R., Xue, C., Johns, R. A., Haywood, G. A., von der Leyen, H. E., Trindade, P. T., Cooke, J. P., Hunt, S. A., et al. (1996) · Circulation · doi:10.1161/01.cir.93.4.720 · Cited by 148 · see citing works
Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway
Ma, Y., Seiler, K. P., Tai, K. F., Yang, L. M., Woods, M. L., & Weis, J. J. (1994) · Infection and Immunity · doi:10.1128/iai.62.9.3663-3671.1994 · Cited by 145 · see citing works
Thalidomide Inhibits Tumor Necrosis Factor α, Decreases Nitric Oxide Synthesis, and Ameliorates the Hyperdynamic Circulatory Syndrome in Portal–Hypertensive Rats
López-Talavera, J. C., Cadelina, G. W., Olchowski, J., Merrill, W., & Groszmann, R. J. (1996) · Hepatology · doi:10.1002/hep.510230644 · Cited by 138 · see citing works
Anticoagulants and Other Preanalytical Factors Interfere in Plasma Nitrate/Nitrite Quantification by the Griess Method
Ricart-Jané, D., Llobera, M., & López-Tejero, M. D. (2002) · Nitric Oxide · doi:10.1006/niox.2001.0392 · Cited by 136 · see citing works
Iron: Mammalian defense systems, mechanisms of disease, and chelation therapy approaches
Kontoghiorghes, G. J., & Weinberg, E. D. (1995) · Blood Reviews · doi:10.1016/0268-960x(95)90038-1 · Cited by 134 · see citing works
Plasma nitrate as an index of nitric oxide formation in man: analyses of kinetics and confounding factors
Jungersten, L., EDLUND, A., Petersson, A.-S., & Wennmalm, Å. (1996) · Clinical Physiology · doi:10.1111/j.1475-097x.1996.tb00726.x · Cited by 135 · see citing works
Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man.
Castillo, L., deRojas-Walker, T., Chapman, T. E., Vogt, J., Burke, J. F., Tannenbaum, S. R., & Young, V. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.1.193 · Cited by 133 · see citing works
Plasma nitric oxide levels in newborn infants with sepsis
Shi, Y., Li, H.-Q., Shen, C.-K., Wang, J.-H., Qin, S.-W., Liu, R., & Pan, J. (1993) · The Journal of Pediatrics · doi:10.1016/s0022-3476(05)81753-6 · Cited by 132 · see citing works
Possible central role of nitric oxide in conditions clinically similar to cerebral malaria
Clark, I. A., Rockett, K. A., & Cowden, W. B. (1992) · The Lancet · doi:10.1016/0140-6736(92)93295-x · Cited by 132 · see citing works
A critical review and discussion of analytical methods in the l-arginine/nitric oxide area of basic and clinical research
Tsikas, D. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.04.018 · Cited by 131 · see citing works
Quantification of nitrite and nitrate in human urine and plasma as pentafluorobenzyl derivatives by gas chromatography—mass spectrometry using their 15N-labelled analogs
Tsikas, D., Böger, R. H., Bode‐Böger, S. M., Gutzki, F. M., & Frölich, J. C. (1994) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/0378-4347(94)00374-2 · Cited by 129 · see citing works
Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome
Wong, H. R., Carcillo, J. A., Burckart, G. J., Shah, N. S., & Janosky, J. E. (1995) · Critical Care Medicine · doi:10.1097/00003246-199505000-00010 · Cited by 129 · see citing works
Cytokines and Lipopolysaccharide Induce Nitric Oxide Synthase in Cultured Rat Pulmonary Artery Smooth Muscle
Nakayama, D. K., Geller, D. A., Lowenstein, C. J., Davies, P. A., Pitt, B. R., Simmons, R. L., & Billiar, T. R. (1992) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb/7.5.471 · Cited by 128 · see citing works
Comparison of nitrite/nitrate concentration in human plasma and serum samples measured by the enzymatic batch Griess assay, ion-pairing HPLC and ion-trap GC–MS: The importance of a correct removal of proteins in the Griess assay
Romitelli, F., Santini, S. A., Chierici, E., Pitocco, D., Tavazzi, B., Amorini, A. M., Lazzarino, G., & Stasio, E. D. (2007) · Journal of Chromatography B · doi:10.1016/j.jchromb.2007.02.003 · Cited by 124 · see citing works
Carbon Monoxide Signaling in Promoting Angiogenesis in Human Microvessel Endothelial Cells
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Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid.
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Authors: Hibbs, J. B., Westenfelder, C., Taintor, R., Vavrin, Z., Kablitz, C., Baranowski, R. L., Ward, J. H., Menlove, R. L., McMurry, M. P., & Kushner, J. P.
Affiliations: Veterans Health Administration (US)
University of Utah (US)
ORCID: Westenfelder, C
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1992-03-01
Volume: 89
Issue: 3
Pages: 867-877
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci115666
PMC: PMC442932
OpenAlex: W2120872446
Cited by: 485
References: 80
Citations by year: 2026: 3 · 2025: 1 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 1 · 2015: 10 · 2014: 7 · 2013: 4 · 2012: 2
FWCI: 36.14
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs
American Heart Association
National Institutes of Health
National Cancer Institute (CA42014, P30CA042014)
National Center for Research Resources (RR 00064)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: nitric oxide production, L-arginine, interleukin-2 therapy, interferon-gamma, TNF-α, interleukin-1, nitrate, urinary nitrate excretion, renal cell carcinoma, melanoma, renal dysfunction, arginine metabolism
MeSH terms: Adult, Arginine, Carcinoma, Renal Cell, Female, Humans, Interferon-gamma, Interleukin-2, Kidney Neoplasms, Kidney Tubules, Male, Melanoma, Middle Aged, Nitric Oxide, Vascular Resistance

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Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy

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