Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product

The human homologue of Drosophila Toll (hToll), also called Toll-like recep tor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor famil y. Interestingly; the TLR4 gene has been localized to the same region to wh ich the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR 4, Macrophages and B cells from TLR4-deficient mice did not respond to LPS, AU these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved a mong the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but no t the mutant TLR4 from C3H/HeJ mice activated NP-kappa B. Taken together, t he present study demonstrates that TLR4 is the gene product that regulates LPS response.