Role of interferon regulatory factor-1 in the regulation of IL-18 production and activity

Interferon regulatory factor-1 (IRF-1) is a transcription factor regulating the expression of several cytokines. Using IRF-1 knockout (KO) mice, the r ole of IRF-1 in the production and activity of IL-18 was evaluated. Adminis tration of IL-12 or concanavalin A significantly increased levels of circul ating IL-18 in wild-type (WT), but not in IRF-1 KO mice. However, despite t hese differences in circulating IL-18 levels, no or only minor differences in constitutive or inducible IL-18 mRNA and tissue-associated protein level s were observed between WT and IRF-1 KO mice. On the other hand, we observe d that constitutive and inducible levels of the IL-18-processing enzyme cas pase-1 were markedly reduced in the spleen and the liver of IRF-1 KO compar ed to WT mice. In addition, both constitutive and inducible liver mRNA leve ls for the IL-18 binding protein (IL-18BP), a specific IL-18 antagonist, we re significantly lower in IRF-1 KO than in WT mice. Compared to IL-12, IL-1 8 only weakly induced IRF-1 mRNA in cultured splenocytes. However, IL-18-in duced IFN-gamma production was strongly reduced in splenocytes from IRF-1 K O compared to WT cells. In conclusion, IRF-1 regulates IL-18 production and activity mostly by modulating expression of caspase-1 and IL-18BP. In addi tion, IRF-1 participates in the induction of IFN-gamma by IL-18.