IL-18 (IFN-GAMMA-INDUCING FACTOR) REGULATES EARLY CYTOKINE PRODUCTIONIN, AND PROMOTES RESOLUTION OF, BACTERIAL-INFECTION IN MICE

IL-12-induced IFN-gamma production is essential for clearance of Yersi nia enterocolitica infection, Similar to IL-12, the recently described cytokine IL-18 (IFN-gamma-inducing factor) is produced by macrophages and induces IFN-gamma production in spleen cells. Therefore, we have investigated the role of IL-18 in Yersinia infection of mice. Heat-kil led yersinia-triggered IL-18-promoted IFN-gamma production of splenocy tes was predominantly dependent on endogenous IL-12 production, wherea s IL-12-promoted IFN-gamma production was not IL-18 dependent, IL-18-i nduced IFN-gamma production was to a higher degree dependent on IFN-ga mma R-mediated mechanisms and in synergism with IL-2 resulted in at le ast fivefold higher IFN-gamma levels as compared with the combination of IL-12 plus IL-2. Analysis of the effect of IL-18 on IL-12 productio n of LPS-stimulated peritoneal macrophages revealed that IL-18 decreas ed LPS-induced IL-12 production, indicating that IL-18 might be involv ed in negative regulation of IL-12 production. In vivo studies reveale d that Yersinia-resistant C57BL/6 mice expressed fourfold higher IL-18 mRNA levels than did susceptible BALB/c mice. Administration of anti- IL-18 Abs caused a 100- to 1000-fold increase in bacterial counts in t he spleen of infected mice but did not change IFN-gamma production lev els. Taken together, our data demonstrate that IL-18 is involved in re gulation of cytokine production during the early phase of bacterial in fections as well as in clearance of Yersinia infection.