Signaling events induced by lipopolysaccharide-activated toll-like receptor 2

Human Toll-like receptor 2 (TLR2) is a signaling receptor that responds to LPS and activates NF-kappa B, Here, we investigate further the events trigg ered by TLR2 in response to LPS. We show that TLR2 associates with the high -affinity LPS binding protein membrane CD14 to serve as an LPS receptor com plex, and that LPS treatment enhances the oligomerization of TLR2, Concomit ant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is re cruited to the TLR2 complex. Intracellular deletion variants of TLR2 lackin g C-terminal 13 or 141 aa fail to recruit IRAK, which is consistent with th e inability of these mutants to transmit LPS cellular signaling. Moreover, both deletion mutants could still form complexes with wild-type TLR2 and ac t in a dominant-negative (DN) fashion to block TLR2-mediated signal transdu ction, DN constructs of myeloid differentiation protein, IRAK, TNF receptor -associated factor 6, and NF-kappa B-inducing kinase, when coexpressed,vith TLR2, abrogate TLR2-mediated NF-kappa B activation. These results reveal a conserved signaling pathway for TLR2 and IL-1Rs and suggest a molecular me chanism for the inhibition of TLR2 by DN variants.