IL-1 Signaling

Interleukin-1 (IL-1) is a pro-inflammatory cytokine that stimulates a broad spectrum of immune responses. IL-1 is produced by activated macrophages, endothelial cells, B cells and fibroblasts. It induces inflammatory responses, edema, promotes the production of prostaglandins, the growth of leukocytes, and expression of IL-2. There are two forms of IL-1 encoded by distinct genes, IL-1α and IL-1β. IL-1β is produced as a 269 amino acid precursor that is cleaved by ICE to its active form which is secreted.The IL-1 receptor consists of two subunits, IL-1R1 and IL-1RAP (IL-1 receptor accessory protein). Upon ligand binding, a complex is formed between IL-1R1 and IL-1RAP. The cytosolic proteins MyD88 and TollIP are recruited to this complex where they function as adaptors, in turn recruiting IRAK and TRAF6. TRAF6 activates two pathways, one leading to NF-κB activation and another leading to c-Jun activation. C-Jun activation is mediated via p38 MAPK and JNK pathways, while NK-κB is activated via the TAB1/TAK1 kinases.Binding of IL-1 to its cell surface receptor also activates G-proteins, which in turn stimulate adenylate cyclase (AC) activity leading to an increase in the intracellular level of cAMP. cyclic AMP activates PKA which then activates the NF-κB pathway. IL-1 is a pivotal pro-inflammatory cytokine centrally involved in local and systemic responses in the immune system which lead to typical effects of inflammation. Its dysregulation, prolonged synthesis and release in chronic inflammation contributes to diseases such as rheumatoid arthritis. IL-1 also augments corticosteroid release and induces fever and shivering.