Essential Role of Interleukin-12 (IL-12) and IL-18 for Gamma Interferon Production Induced by Listeriolysin O in Mouse Spleen Cells

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Abstract
The mechanism of gamma interferon (IFN-γ) production induced by listeriolysin O (LLO), a cytolytic virulence factor ofListeria monocytogenes, was analyzed with special reference to the involvement of macrophage-derived cytokines in spleen cells of mice. LLO purified from the culture supernatant ofL. monocytogeneswas capable of inducing a high level of IFN-γ when its cytolytic activity was blocked by cholesterol treatment. The IFN-γ-inducing ability of LLO was not dependent on possibly contaminating lipopolysaccharide. Depletion of CD11b+cells resulted in a profound decrease in IFN-γ production in response to LLO stimulation. Negative selection also suggested the contribution of DX5+cells in IFN-γ production. Reverse transcription-PCR revealed that expression of interleukin-12 (IL-12) p35 and p40 was induced by LLO but that the IL-18 mRNA level in the CD11b+fraction of spleen cells was unchanged. There was no change in the expression of the IFN-γ-inducing cytokine genes in the CD11b−fraction. Neutralization of IL-12 and IL-18 in culture abolished the IFN-γ production almost completely. Spleen cells from IL-12- or IL-18-deficient mice never produced IFN-γ after stimulation with LLO. These results clearly indicated that LLO, a well-known virulence factor ofL. monocytogenes, is capable of inducing IFN-γ from NK cells through induction of IL-12 and IL-18 from macrophages. LLO appeared to play essential roles, not only as a bacterial virulence factor but also as a bacterial modulin in the immune response of the host.