Interleukin-2-induced nitric oxide synthase and nuclear factor-kappaB activity in activated natural killer cells and the production of interferon-gamma.
We have previously shown that inducible nitric oxide synthase (iNOS) was up-regulated in natural killer (NK) cells when AK-5 tumour cells were transplanted subcutaneously into syngeneic Wistar rats. This study was designed to investigate the role of interleukin (IL)-2 during the induction of iNOS and to understand the subsequent events involved in NK cell activation. There was up-regulation of iNOS expression when naïve NK cells were cultured in the presence of recombinant IL-2. These NK cells produced a higher nitrite content and possessed cytotoxic activity against YAC-1 and AK-5 tumour cells. Induction of iNOS enhanced nuclear factor (NF)-kappaB binding activity in IL-2 activated NK cells, which was confirmed using L-NAME, an NO synthesis inhibitor. Addition of L-NAME along with rIL-2 significantly blocked NF-kappaB activity and also down-regulated the production of NO and the cytotoxic activity of NK cells. Furthermore, injection of anti-IL-2 antibody in subcutaneous tumour transplanted animals abrogated significantly the expression of iNOS and NF-kappaB activity, leading to reduced NO production and cytotoxic activity of NK cells against YAC-1 and AK-5 cells. In addition, the expression of interferon (IFN)-gamma by NK cells was also inhibited in anti-IL-2 antibody injected animals compared with the control animals. Finally, there was enhanced tumour growth and delayed regression in anti-IL-2 injected animals compared with control animals.
Centre for Cellular & Molecular Biology, Hyderabad, India.
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D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000906:Antibodies; D007376:Interleukin-2; D016328:NF-kappa B; D009573:Nitrites; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat