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

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 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-γ.