The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense

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Science's STKE  25 Feb 2003:
Vol. 2003, Issue 171, pp. re3
DOI: 10.1126/stke.2003.171.re3

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The interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily plays a central role in inflammation and the host response to bacterial infection. It includes receptors for the cytokines IL-1 and IL-18, which are secreted during inflammation and during infection in response to microbial products. Products released by a diverse range of microbes act through TLRs, a notable example being lipopolysaccharide (LPS) from gram-negative bacteria, which stimulates TLR-4. Recognition of such microbes by TLRs provokes host defenses against these microbes. Members of the TLR family occur in species from diverse taxa, including mammals, plants, and insects. In insects, receptors such as Toll are also involved in development. The Toll-IL-1 receptor (TIR) domain occurs in the cytosolic region of all superfamily members and triggers the activation of transcription factors, such as nuclear factor κB (NF-κB). It also activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun NH2-terminal kinase (JNK). These signals lead to increased expression of proteins involved in immunity and inflammation, resulting in defenses against infectious agents or to chronic inflammation in autoimmune diseases. NF-κB binding sites occur in the promoters of a large number of immune genes, and the signaling pathway to NF-κB is known in detail. Also being uncovered are differences in signaling between TLRs that lead to the tailoring of innate immune responses to the provoking pathogen. The IL-1R/TLR system is therefore evolutionarily conserved and is a critical determinant of innate immune and inflammatory responses.