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-1 beta

IL-18, produced as biologically inactive precursor, is secreted from LPS-st imulated macrophages after cleavage by caspase-1, In this study, we investi gated the mechanism underlying caspase-1-mediated IL-18 secretion. Kupffer cells constantly stored IL-18 and constitutively expressed caspase-1, Inhib ition of new protein synthesis only slightly reduced IL-18 secretion, while it decreased and abrogated their IL-1 beta and IL-12 secretion, respective ly. Kupffer cells deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did not secrete IL-18, IL-1 beta, and IL-12 upon LPS stimulation . In contrast, Kupffer cells lacking myeloid differentiation factor 88 (MyD 88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18 without IL-1 beta and IL-12 production in a caspase-1-dependent and de novo synthe sis-independent manner. These results indicate that MyD88 is essential for IL-12 and IL-IP production from Kupffer cells while their IL-18 secretion i s mediated via activation of endogenous caspase-1 without de novo protein s ynthesis in a MyD88-independent fashion after stimulation with LPS, In addi tion, infection with Listeria monocytogenes, products of which have the cap acity to activate TLR, increased serum levels of IL-18 in wild-type and MyD 88-deficient mice but not in caspase-1-deficient mice, whereas it induced e levation 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 sugges ted caspase-1-dependent, MyD88-independent IL-18 release in bacterial infec tion.