Generation and analyses of endotoxin hyporesponsive knockout mice.

Toll in Drosophila is a receptor that is required for dorsoventral polarity during development, and also involved in host defence against fungal infection. Recently, mammalian homologues of Toll, designated as Toll-like receptors (TLRs) have been identified. The TLR family harbors an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic domain that is homologous to that of the IL-1R family. Analogous to the IL-1R, TLR recruits IRAK via adaptor MyD88, and then induces activation of TRAF6, NIK and finally NF-κB.In order to examine the role of TLR family, we have generated mice lacking TLR2, TLR4, and MyD88. TLR4 KO mice are hyporesponsive to LPS. On the other hand, TLR2 KO mice are hyporesponsive to peptidoglycan from gram-positive bacteria, but not to LPS. MyD88 KO mice are unresponsive to LPS. Taken together, these results demonstrate that responses to bacterial cell wall components are differentially mediated by TLR2 and TLR4, and that LPS signaling is mediated by TLR4 via MyD88.