Lipopolysaccharide-Induced IL-18 Secretion from Murine Kupffer Cells Independently of Myeloid Differentiation Factor 88 That Is Critically Involved in Induction of Production of IL-12 and IL-1β

• Published in: The Journal of immunology (1950) 2001-02, Vol.166 (4), p.2651-2657
• Main Authors: Seki, Ekihiro, Tsutsui, Hiroko, Nakano, Hiroki, Tsuji, Noriko M., Hoshino, Katsuaki, Adachi, Osamu, Adachi, Keishi, Futatsugi, Shizue, Kuida, Keisuke, Takeuchi, Osamu, Okamura, Haruki, Fujimoto, Jiro, Akira, Shizuo, Nakanishi, Kenji
• Format: Article
• Language: English
• Subjects: Interleukin 1^b; MyD88 protein; myeloid differentiation factor
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.4.2651

IL-18, produced as biologically inactive precursor, is secreted from LPS-stimulated macrophages after cleavage by caspase-1. In this study, we investigated the mechanism underlying caspase-1-mediated IL-18 secretion. Kupffer cells constantly stored IL-18 and constitutively expressed caspase-1. Inhibition of new protein synthesis only slightly reduced IL-18 secretion, while it decreased and abrogated their IL-1β and IL-12 secretion, respectively. Kupffer cells deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did not secrete IL-18, IL-1β, and IL-12 upon LPS stimulation. In contrast, Kupffer cells lacking myeloid differentiation factor 88 (MyD88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18 without IL-1β and IL-12 production in a caspase-1-dependent and de novo synthesis-independent manner. These results indicate that MyD88 is essential for IL-12 and IL-1β production from Kupffer cells while their IL-18 secretion is mediated via activation of endogenous caspase-1 without de novo protein synthesis in a MyD88-independent fashion after stimulation with LPS. In addition, infection with Listeria monocytogenes, products of which have the capacity to activate TLR, increased serum levels of IL-18 in wild-type and MyD88-deficient mice but not in caspase-1-deficient mice, whereas it induced elevation of serum levels of IL-12 in both wild-type and caspase-1-deficient mice but not in MyD88-deficient mice. Taken together, these results suggested caspase-1-dependent, MyD88-independent IL-18 release in bacterial infection.