Negative regulators in Toll-like receptor responses.

Innate immune responses are initiated by pattern recognition receptors, which recognize specific structures of microorganisms. Among them, toll-like receptors (TLRs) are capable of sensing organisms ranging from viruses to bacteria, fungi, and protozoa and play major roles in innate immunity. TLR activation controls complex gene expression networks that regulate the magnitude and duration of the immune reaction. Autophagy, a bulk degradation system that delivers cytoplasmic constituents in the lysosome, controls degradation of long-lived proteins, insoluble protein aggregates, and invading pathogens. We recently generated mutant mice lacking Atg16L1, an autophagy-related gene that is implicated in Crohn's disease, and thereby examined its role in TLR-mediated inflammatory response. Atg16L1 was indispensable for the formation of autophagosomes and suppression of endotoxin-induced interleukin (IL)-1 production, suggesting that it is responsible for the control of endotoxin-mediated inflammatory responses. Because TLR ligands have been identified and TLR signaling pathways clarified, we are now looking at the effector phase of TLR responses. We are starting to generate knockout (KO) mice of the genes that are induced in response to TLR stimulation, but whose functions are unknown. Among them, we recently identified a novel gene, Zc3h12a, encoding a nuclease involved in destabilization of IL-6 and IL-12 messenger RNAs. KO mice lacking this gene developed spontaneous autoimmune diseases accompanied by splenomegaly and lymphadenopathy. This review describes the phenotypes of our different KO mice models and the role of various molecules in TLR responses.