NK cells secrete high levels of IFN-gamma in response to in vivo administration of IL-2.
Interleukin-2 is an immunotherapeutic agent for the treatment of metastatic tumors. Administration of recombinant human IL-2 (rhIL-2) in vivo activates lymphocytes and cell-mediated immune responses. In mice, we have recently observed a dramatic increase of serum IFN-gamma levels in response to in vivo administration of rhIL-2, which was necessary for the observed protective effects of IL-2 against the development of collagen-induced arthritis. To explore further the basis of this phenomenon, the kinetics and source of IFN-gamma in response to IL-2 was investigated. Highest serum levels of IFN-gamma were observed within 3 h of IL-2 administration, with levels decreasing over time. Anti-IL-2 receptor beta antibody blocked this IFN-gamma induction. Multiple doses of rhIL-2 resulted in corresponding increases in circulating IFN-gamma. IFN-gamma induction was dose-dependent between doses of 240 to 30,000 U of rhIL-2. Analysis of the cellular source of IFN-gamma secretion using NK- and T cell-deficient mice demonstrated that NK cells are the likely source of IFN-gamma. Furthermore, IFN-gamma secretion in response to IL-2 administration was not affected by the absence of IL-12, the pivotal cytokine for determination of Th1 responses. These results suggest that effects of IL-2 on immune responses in vivo may be mediated by IFN-gamma.
Thornton
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William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Kuhn
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Finkelman
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Hirsch
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D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000494:pharmacology
D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma