The Interleukin-1 Family: A Key Regulator in the Pathogenesis of Psoriasis

Interleukin-1 (IL-1) family members, as most potent molecules of the innate immune system, are key regulators of multiple inflammatory diseases. The family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL- 33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL- 38), and one anti-inflammatory cytokine (IL-37). Most of these cytokines are abundantly expressed in skin under the regulation of IL-17 and act on innate immune cells to influence their survival and function. This review provides an overview of all the members of the IL-1 family and its potential regulatory roles in the pathogenesis of psoriasis. Th17 cell-mediated immune disease. Increasing evidence from experimental and clinical findings points to the important function of IL-1 family and IL-17 in the pathogenesis of psoriasis (3-8). Most of IL-1 family members have been reported constitutively expressed by keratinocytes in vivo and shown to be highly expressed in the psoriatic skin (9-12). This increasing expression of IL-1 family members contributes to Th17 cell development, leading to the production of IL-17 (13,14). Therefore, IL-1 family is considered as an important mediator in the initiation and maintenance of psoriatic plaques. However, not only IL-1 family induces Th17 cells to produce IL-17, IL-17 in turn can act on keratinocytes to produce more IL-1 family cytokines (15,16). These observations thereby indicate that the IL-17/IL-1 axis plays important roles in the pathogenesis of psoriasis. In this review, we summarize the experimental and clinical findings to consolidate our understanding on the function of IL-1 family members in psoriasis. IL-1 Family and Psoriasis IL-1 subfamily IL-1α and IL-1β: IL-1α (IL-1F1) and IL-1β (IL-1F2) are the first two members of IL-1 family discovered. Despite their identical activities, IL-1α and IL-1β have several differences. Firstly, IL-1β is secreted and circulates systemically, whereas IL-1α is generally innate immunity and inflammation, play a key role in the biology of multiple inflammatory diseases. So far, 11 members of the IL-1 family have been identified, including seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and one anti- inflammatory cytokine (IL-37) (Table 1). According to the length of their precursor and the propiece for each precursor, the IL-1 family can also be categorized into three subfamilies including IL-1, IL-36 and IL-18. IL-1 family members signal through a group of closely related receptor complexes: IL-1R1 and IL-1RAcP complex as IL- 1α/β receptor, ST2 and IL-1RAcPcomplex as IL-33 receptor, IL-18Rα and IL-18Rβ complex as IL-18 receptor, and IL-1Rrp2 and IL-1RAcP complex as IL-36 receptor. The activation of these receptor complexes initiates and/or amplifies innate immune responses. Three other IL-1 receptor family members are IL-1R2, IL18BP and SIGIRR (also known as TIR8), which all act as negative regulators of IL-1 signaling