Interferon gamma and interleukin 2 synergize to induce selective monokine expression in murine peritoneal macrophages

We have examined the effects of interleukin 2 (IL-2) treatment either alone or in combination with interferon (IFN) gamma or beta on the expression of several activation associated genes (e.g. tumor necrosis factor alpha (TNF alpha), IFN-inducible 10-kDa protein (IP-10] in murine peritoneal macrophages. IL-2 alone did not induce the expression of either gene while IFN gamma or IFN beta had a modest inductive effect on IP-10 but no effect on TNF alpha expression. When either form of IFN was used in combination with IL-2 there was a marked synergistic induction of both mRNAs. IFN gamma and IL-2 were maximally effective when both agents were added simultaneously, and induced mRNA expression declined over a 24-h period in cells pretreated with IFN gamma prior to addition of IL-2. Expression of both genes following combination lymphokine treatment was mediated by increased transcriptional activity. The responses to all three lymphokines were dose dependent; the concentration requirement for IL-2 indicated interaction with an intermediate or low affinity receptor. The expression of both monokine genes was transient and was comparable although not identical to that seen in cells stimulated with lipopolysaccharide. IFN gamma and IL-2 could synergize to stimulate the expression of either TNF alpha or IP-10 mRNA using sequential non-overlapping treatment periods regardless of the order in which the two stimuli were applied to the cells. The effect of either agent alone induced a transient (1-5 h) responsive state with respect to subsequent stimulation with the second agent. Expression of both monokine genes in response to IFN gamma/IL-2 treatment was independent of protein synthesis as cycloheximide did not inhibit the accumulation of specific mRNA. Interestingly, the combination of IL-2 and cycloheximide was as effective as IFN gamma and IL-2 together. In concert, these results indicate that both IFN and IL-2 generate independent intracellular signals which alone are incapable of inductive effect but which are potent activators of inflammatory gene expression when coincidentally expressed.