IL-1 Family Signaling Pathways

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Overview of the IL-1 Family Signaling Pathway

The IL-1 cytokine family consists of eleven members that play important roles in regulating inflammation. Members include IL-1 alpha, IL-1 beta, IL-1ra, IL-18, IL-33, IL-36Ra, IL-36 alpha, IL-36 beta, IL-36 gamma, IL-37, and IL-38. While most of these cytokines are biologically active as full-length molecules, activation and secretion of IL-1 beta and IL-18 requires inflammasome/Caspase-1-dependent processing. Other IL-1 family cytokines do not require Caspase-1 cleavage for activation but may undergo some form of protease processing since more potent forms of many of these cytokines can be generated by trimming amino acids at their N-terminal ends.

IL-1 family cytokines mediate their effects by binding to a primary IL-1 family receptor subunit, such as IL-1 RI, IL-18 R alpha, IL-1 Rrp2, or ST2, which subsequently recruits an accessory receptor, IL-1 RAcP or IL-18 R beta, to activate downstream signaling. IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, and IL-36 gamma trigger intracellular signaling cascades that induce the NF-kappa B- and AP-1-dependent expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response. In addition, unprocessed forms of IL-1 alpha and IL-33 and the mature form of IL-37b can translocate to the nucleus where they may act as transcriptional regulators. In contrast to the pro-inflammatory members of the IL-1 family, IL-1ra, IL-36Ra, IL-37, and IL-38 have anti-inflammatory effects. IL-1ra antagonizes IL-1 activity by binding to IL-1 RI. This prevents IL-1 alpha and IL-1 beta from interacting with their primary receptor subunit and inhibits recruitment of IL-1 RAcP. Similarly, IL-36Ra binds to IL-1 Rrp2 and inhibits IL-36 signaling. Less is known about IL-37 and IL-38, but both have also been suggested to have anti-inflammatory effects. Five splice variants of IL-37 (IL-37a-e) exist with four containing a putative Caspase-1 cleavage site. Both the immature and mature forms of the longest isoform, IL-37b, bind to IL-18 binding protein (IL-18 BP) and enhance its ability to inhibit IL-18 activity. IL-38 binds to the IL-36 receptor, IL-1 Rrp2, and soluble IL-1 RI. Initial data suggests that the interaction between IL-38 and IL-1 Rrp2 has anti-inflammatory effects similar to those induced by IL-36Ra.

In addition to IL-1ra and IL-36Ra, the pro-inflammatory effects of IL-1, IL-18, IL-33, and IL-36 are regulated by several other endogenous inhibitors. IL-I RII is an IL-1 family receptor that, unlike other receptors in this family, lacks a TIR domain. It can bind to IL-1 alpha and IL-1 beta and recruit IL-1 RAcP, but it is incapable of transducing a signal. As a result, it acts as an IL-1 decoy receptor. Soluble IL-1 RI and IL-I RII can also bind to IL-1 alpha and IL-1 beta and recruit IL-1 RAcP but cannot activate intracellular signaling. Similarly, soluble ST-2/IL-1 R4 and soluble IL-18 R alpha have been shown to negatively regulate IL-33 and IL-18 signaling, respectively. IL-18 signaling is also regulated by IL-18 BP. IL-18 BP is a soluble protein that binds to IL-18 with higher affinity than either the cell-bound or soluble forms of IL-18 R and prevents IL-18 signaling. Single immunoglobulin domain containing IL-1 receptor-related (SIGIRR) molecule is another potential endogenous inhibitor of IL-1, IL-18, IL-33, and IL-36 signaling. SIGIRR is a transmembrane protein with one extracellular Ig-like domain that has been shown to bind to several IL-1 family cytokines and inhibit signaling in a context-dependent manner.

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