NK cells secrete high levels of IFN-γ in response toin vivo administration of IL-2

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Abstract
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‐γ 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‐γ in response to IL‐2 was investigated. Highest serum levels of IFN‐γ were observed within 3 h of IL‐2 administration, with levels decreasing over time. Anti‐IL‐2 receptor β antibody blocked this IFN‐γ induction. Multiple doses of rhIL‐2 resulted in corresponding increases in circulating IFN‐γ. IFN‐γ induction was dose‐dependent between doses of 240 to 30,000 U of rhIL‐2. Analysis of the cellular source of IFN‐γ secretion using NK‐ and T cell‐deficient mice demonstrated that NK cells are the likely source of IFN‐γ. Furthermore, IFN‐γ secretion in response to IL‐2 administration was not affected bythe 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‐γ.