Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy.
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.
Hibbs
J B
JB
Medical Service, Veterans Affairs Medical Center, Salt Lake City, Utah.
Westenfelder
C
C
Taintor
R
R
Vavrin
Z
Z
Kablitz
C
C
Baranowski
R L
RL
Ward
J H
JH
Menlove
R L
RL
McMurry
M P
MP
Kushner
J P
JP
D000328:Adult; D001120:Arginine / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000628:therapy; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000378:metabolism / Q000628:therapy; D007684:Kidney Tubules / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000628:therapy; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects
D007376:Interleukin-2; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine