IL-1 Family

The IL-1 family of cytokines consists of eleven members (IL-1F1-IL-1F11) that share a conserved beta-trefoil structure and bind to receptors belonging to the IL-1 receptor family. With the exception of IL-1ra/IL-1F3, IL-1 family cytokines lack a signal peptide and therefore, are not thought to be secreted by the conventional endoplasmic reticulum/Golgi-dependent secretory pathway used by other cytokines. IL-1 beta/IL-1F2 and IL-18/IL-1F4 are synthesized as inactive precursor proteins that are activated and secreted following cleavage by Caspase-1. Other IL-1 family cytokines are biologically active as full-length molecules, including IL-1 alpha/IL-1F1, IL-33/IL-1F11, IL-36Ra/IL-1F5, IL-36 alpha/IL-1F6, IL-36 beta/IL-1F8, and IL-36 gamma/IL-1F9, but processing of many of these cytokines at their N-terminal ends generates more potent forms, indicating that they may also undergo processing in vivo.

IL-1 family cytokines activate intracellular signaling pathways by binding to a primary receptor subunit, such as IL-1 RI/IL-1 R1, IL-18 R alpha/IL-1 R5, IL-1 Rrp2/IL-1 R6, or ST2/IL-1 R4, which then recruits an accessory receptor to form the active receptor complex. Signaling cascades triggered by IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, or IL-36 gamma activate MAPKs and NF-kappa B, leading to the expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response. In addition, several of these cytokines have been shown to regulate the differentiation and function of T helper cells. Other members of the IL-1 family inhibit inflammation by functioning as antagonists of IL-1 or IL-36 signaling. IL-1ra negatively regulates IL-1 signaling by binding to IL-1 RI and inhibiting its ability to interact with IL-1 alpha and IL-1 beta. Similarly, IL-36Ra binds to IL-1 Rrp2 and inhibits IL-36 signaling. Both IL-37/IL-1F7 and IL-1F10/IL-38 have also been suggested to have anti-inflammatory effects.