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

Abstract

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.

Fas ligand–induced caspase-1–dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease

“…As previously reported, pro-IL-18 is stored in Kupffer cells, 22 and IL-18 requires cleavage for its secretion by appropriate enzymes that are distinct depending on the sorts of stimuli. 7,8,11 The molecular basis of the processing of IL-18 is still unknown.…”

“…A recent study demonstrated that upon stimulation with LPS, caspase-1 is activated via Toll-like receptor (TLR)-4, a signaling receptor for LPS, but independently of myeloid differentiation factor-88, an adaptor molecule for TLR-mediated signaling, leading to IL-18 secretion. 22 However, we do not yet know the signaling pathway after TLR-4 activation. This is also the case for FasL-induced IL-18 secretion.…”

Cutting Edge: Protective Cell-Mediated Immunity to Listeria monocytogenes in the Absence of Myeloid Differentiation Factor 88

“…Whether this is unique to LM, to other cytoplasmic intracellular pathogens, or is a more general property of infection vs immunization is uncertain. Perhaps this is the same pathway that accounts for MyD88-independent production of IL-18 observed following LM infection in mice (20), and production of IFN-␤ in macrophages when LM gains access to the cytoplasm (21,22). It is tantalizing to hypothesize that the key difference in induction of specific immunity between LM infection and the administration of soluble Ag lies in the ability of LM to gain access to the intracytoplasmic cellular compartment, and thereby activate classes of Ag sensing molecules unique to this compartment.…”

The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases

“…Accordingly, Kupffer cells express TLR4 and are responsive to LPS [18]. Upon triggering, TLR4 signaling drives Kupffer cells to produce TNF-a, IL-1b, IL-6, IL-12, IL-18, and antiinflammatory cytokine IL-10 [19].…”