title: Inducible nitric oxide synthase (iNOS) is not required for IL-2-induced hypotension and vascular leak syndrome in mice.
abstract: Dose limiting side effects of interleukin-2 (IL-2) include severe hypotension and vascular leak syndrome (VLS). Previous studies have shown that nitric oxide (NO) synthesis is strongly induced after IL-2 treatment of C3H/HeN mice (180,000 IU b.i.d. for 5 d). We employed knockout mice (on C57BL/6 background) to test the role of the inducible NO synthase (iNOS) in mediating IL-2 toxicity. In contrast to C3H/HeN mice, which developed hypotension and VLS after 10 doses of only 180,000 IU IL-2, C57BL/6 mice were far more resistant requiring increased doses of 800,000 IU IL-2 (b.i.d., 5 d) to induce hypotension and VLS. Serum interferon-gamma levels were significantly more elevated by IL-2 treatment in C3H/HeN mice than in C57BL/6, correlating with the severity of hypotension and VLS. Urinary excretion of NO metabolites was markedly reduced in iNOS knockout mice (C57BL/6 iNOS) after IL-2 treatment. A surprising finding was that these mice still developed profound hypotension and VLS. Similar findings were observed after administration of a iNOS specific inhibitor, L-N[6]-(1-iminoethyl)lysine (L-NIL). In contrast, a general NOS inhibitor, N-monomethyl-L-arginine, prevented both hypotension and vascular leak. The superoxide dismutase mimetic, M40403, reversed IL-2-induced hypotension but not VLS in knockout mice. Thus, peroxynitrite-mediated mechanisms are likely responsible for hypotension, whereas NO-induced changes in vascular permeability result in VLS. The iNOS enzyme is not necessary for pathogenesis of IL-2-induced cardiovascular toxicity. These results imply that other NOS isoforms, such as endothelial NOS, may play a major role in the development of IL-2-induced cardiovascular toxicity.
authors.affiliation: Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Kondapaneni
authors.forename: John R
authors.initials: JR
authors.lastname: McGregor
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
authors.forename: Wolfram E
authors.initials: WE
authors.lastname: Samlowski
mesh_terms: D000818:Animals; D019559:Capillary Leak Syndrome / Q000139:chemically induced* / Q000201:enzymology*; D002199:Capillary Permeability / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D007022:Hypotension / Q000139:chemically induced* / Q000201:enzymology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008345:Manganese; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D007376:Interleukin-2; C090663:N(6)-(1-iminoethyl)lysine; D009942:Organometallic Compounds; D019323:omega-N-Methylarginine; C121876:imisopasem manganese; D009569:Nitric Oxide; D008345:Manganese; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D008239:Lysine