Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

초록

Innate immunity, which is the first line of host defense against invading microbial pathogens in multicellular organisms, occurs through germline-encoded pattern-recognition receptors. The Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily comprises proteins that contain the phylogenetically conserved Toll/IL-1 receptor (TIR) domain, which is responsible for the propagation of downstream signaling through recruitment of TIR domain containing cytosolic adaptor proteins such as MyD88, TIRAP/MAL, TRIF, TRAM and SARM. These interactions activate transcription factors that regulate the expression of various proinflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) and chemokines. Activation of the TLR/IL-1R signaling pathway promotes the onset of inflammatory diseases, autoimmune diseases and cancer; therefore, this pathway can be used for the development of therapeutic strategies against these types of pathogenesis. In this review paper, we illustrate the role of the TIR–TIR domain interaction with the TLR/IL-1R signaling pathway in inflammation and apoptosis and recent therapeutic drugs targeted to inhibit the downstream signaling cascade for treatment of inflammatory diseases and cancer.

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