Nitric oxide synthesis contributes to IL-2-induced antitumor responses against intraperitoneal Meth A tumor

C. Y. Yim, J. R. McGregor, O. D. Kwon, N. R. Bastian, M. Rees, M. Mori, J. B. Hibbs, W. E. Samlowski

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Abstract

IL-2 therapy is a potent inductive stimulus for nitric oxide (NO·) synthesis in mice and humans. It is not yet clear whether NO· can contribute to IL-2-induced therapeutic responses. The murine skin cancer Meth A is relatively resistant to lymphokine-activated killer (LAK) cell killing, allowing evaluation of the role of IL-2-induced NO· synthesis in vivo, without contribution by LAK cells. Subcutaneous IL-2 treatment of mice bearing i.p. Meth A tumor increased nitrite production by cells derived from ascites (63 ± 14 μM vs 3.2 ± 1.5 μM in untreated controls). N(ω)- monomethyl-L-arginine (MLA), NO· synthase inhibitor, prevented this increase. NO· production correlated in an inverse fashion with tumor cell proliferation in vitro. Evidence for IL-2-induced heme nitrosylation was demonstrated in tumor cells by electron paramagnetic resonance spectroscopy. By immunomagnetic depletion experiments, macrophages were implicated as a major source of NO· synthesis. Cytologic and flow-cytometric evaluation revealed that IL-2 treatment resulted in enhanced lymphocyte and macrophage recruitment into malignant ascites, and decreases in tumor cell recovery. MLA administration further increased host cell recovery. Subcutaneous IL-2 therapy increased urinary nitrate excretion up to eightfold in mice, and appeared to produce a significant survival advantage that was prevented by MLA administration.

Original languageEnglish (US)
Pages (from-to)4382-4390
Number of pages9
JournalJournal of Immunology
Volume155
Issue number9
StatePublished - Jan 1 1995

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Yim, C. Y., McGregor, J. R., Kwon, O. D., Bastian, N. R., Rees, M., Mori, M., Hibbs, J. B., & Samlowski, W. E. (1995). Nitric oxide synthesis contributes to IL-2-induced antitumor responses against intraperitoneal Meth A tumor. Journal of Immunology, 155(9), 4382-4390.