Toll-like receptors; their physiological role and signal transduction system

Drosophila Toll protein is a transmembrane receptor whose function is to re cognize the invasion of microorganisms as well as to establish dorso-ventra l polarity. Recently, mammalian homologues of Toll. designated as Toll-like receptors (TLRs) have been discovered. So far, six members (TLRI-6) have b een reported and two of these, TLR2 and TLR4, have been shown to be essenti al for the recognition of distinct bacterial cell wall components. TLR2 dis criminates peptidoglycan (PGN), lipoprotein, lipoarabinomannan (LAM) and zy mosan, whereas TLR4 recognizes lipopotysaccharide (LPS), lipoteichoic acid (LTA) and Taxol. Bacterial components elicit the activation of an intracell ular signaling cascade via TLR2 in a similar way to that occurs upon ligand binding to IL-I receptor (IL-IR). This signaling pathway leads to the acti vation of a transcription factor NF-kappaB and c-Jun N-terminal kinase (JNK ), which initiate the transcription of proinflammatory cytokine genes. Part icularly, analysis of knockout mice revealed a pivotal role for MyD88 in th e signaling of the TLR/IL-1R family. Taken together, TLRs and the downstrea m signaling pathway play a key role in innate immune recognition and in sub sequent activation of adaptive immunity. (C) 2001 Published by Elsevier Sci ence B.V.