Co-operative induction of pro-inflammatory signaling by Toll-like receptors

Toll-like receptors (TLRs) mediate detection of a broad range of pathogens and pathogen-derived products including LPS, peptidoglycan, bacterial Lipop eptides, and lipoteichoic acid. Recent evidence indicates that the broad sp ecificity of TLRs may be a consequence of the interactions between differen t TLRs. In this report, we demonstrate that while a constitutively active T LR4 homodimer can induce the production of pro-inflammatory cytokines, homo dimers of TLR2 and TLR6 cannot. However, when co-expressed in the same cell , constitutively active TLR2 and TLR6 strongly induce cytokine production, indicating that these TLRs require partners to productively signal. Since T LR4 signals as a homodimer, while TLR2 and TLR6 do not, it is clear that, d espite the conservation of their cytoplasmic signaling domains, the mechani sms by which they initiate signaling are different. We have localized the r egion of TLR4 that mediates its ability to signal as a homodimer to the mem brane-proximal half of the cytoplasmic tail of the receptor.