The IL-1 family of cytokines and receptors in rheumatic diseases

More than any other cytokine family, the 11 members of the IL-1 family are associated with innate immune responses, which occur in acute inflammation and chronic inflammatory conditions such as rheumatic diseases. In many rheumatic diseases, the severity of the condition can result from the balance between the pro-inflammatory and anti-inflammatory members of the IL-1 family. Pro-inflammatory family members (IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta and IL-36 gamma) are found in the articular environment during arthritis and often correlate with the degree of inflammation present. IL-1 beta has emerged as pivotal for promoting inflammation, particularly in autoinflammatory diseases, whereas IL-1 alpha and the IL-36 subfamily are associated with skin diseases. IL-33 regulates T helper 2 (T(H)2) cell-mediated diseases, in sharp contrast to IL-18, which mainly regulates T(H)1 cell-mediated responses. The IL-1 family also contains four members that suppress inflammation: two specific receptor antagonists (IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra)), and two members that broadly suppress innate inflammation by non-specifically reducing several cytokines and chemokines (IL-37 and IL-38). In this Review, each of the eleven IL-1 family cytokines and their receptors are discussed, along with their putative roles in rheumatic disease and therapeutic options for targeting or promoting these cytokines.