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Dependency of Caspase-1 Activation Induced in Macrophages by Listeria monocytogenes on Cytolysin, Listeriolysin O, after Evasion from Phagosome into the Cytoplasm¹

Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Listeriolysin O (LLO), an hly-encoded cytolysin from Listeria monocytogenes, plays an essential role in the entry of this pathogen into the macrophage cytoplasm and is also a key factor in inducing the production of IFN- during the innate immune stage of infection. In this study, we examined the involvement of LLO in macrophage production of the IFN--inducing cytokines IL-12 and IL-18. Significant levels of IL-12 and IL-18 were produced by macrophages upon infection with wild-type L. monocytogenes, whereas an LLO-deficient mutant (the L. monocytogenes hly) lacked the ability to induce IL-18 production. Complementation of hly with hly completely restored the ability. However, when hly was complemented with ilo encoding ivanolysin O (ILO), a cytolysin highly homologous with LLO, such a restoration was not observed, although ILO-expressing L. monocytogenes invaded and multiplied in the macrophage cytoplasm similarly as LLO-expressing L. monocytogenes. Induction of IL-18 was diminished when pretreated with a caspase-1 inhibitor or in macrophages from caspase-1-deficient mice, suggesting the activation of caspase-1 as a key event resulting in IL-18 production. Activation of caspase-1 was induced in macrophages infected with LLO-expressing L. monocytogenes but not in those with hly. A complete restoration of such an activity could not be observed even after complementation with the ILO gene. These results show that the LLO molecule is involved in the activation of caspase-1, which is essential for IL-18 production in infected macrophages, and suggest that some sequence unique to LLO is indispensable for some signaling event resulting in the caspase-1 activation induced by L. monocytogenes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Culture and Sports of Japan, a Grant-in-Aid for Scientific Research (B) and (C), and a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science.

² Address correspondence and reprint requests to Dr. Masao Mitsuyama, Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshida-konoecho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail address: mituyama{at}mb.med.kyoto-u.ac.jp

³ Abbreviations used in this paper: LM, Listeria monocytogenes; ILO, ivanolysin O; LI, Listeria ivanovii; LDH, lactate dehydrogenase; LLO, listeriolysin O; MOI, multiplicity of infection; NLR, Nod-like receptor; PEC, peritoneal exudate cell; PEST, Pro-Glu-Ser-Thr; z-YVAD-fmk, N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone.

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