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

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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, McMurry, M P, Kushner, J P·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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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 (medical) › 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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