Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases.
Roles for Toll-like receptors (TLRs) are emerging in conditions such as sepsis syndrome, systemic lupus erythromatosis, rheumatoid arthritis and asthma, suggesting that the selective targeting of TLRs might be useful therapeutically. TLRs are defined by the presence of extracellular leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain, and play a role in host defence and inflammation. Signalling pathways activated by TLRs show remarkable similarity to those activated by the pro-inflammatory cytokine interleukin-1 (the receptor for which also has a Toll/interleukin-1 receptor domain), although adaptor proteins specific for certain TLRs are starting to emerge (e.g. Mal and Trif). The common signalling pathways used by all members of the TLR superfamily are being targeted, with drugs that block nuclear factor-kappaB and p38 mitogen-activated protein kinase in clinical development for diseases such as rheumatoid arthritis and psoriasis. As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting.
O'Neill
Luke A J
LA
Cytokine Research Group, Department of Biochemistry, Trinity College Dublin, Ireland. laoneill@tcd.ie
D000818:Animals; D003141:Communicable Diseases / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D015398:Signal Transduction; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D051193:Toll-Like Receptors