Interleukin-36 Receptor Antagonist (IL-36Ra) is a member of the interleukin-36 family of cytokines, which are part of the larger IL-1 superfamily. The IL-36 family includes three agonists (IL-36α, IL-36β, and IL-36γ) and one antagonist (IL-36Ra). These cytokines play crucial roles in inflammatory responses and immune regulation .
IL-36Ra functions as a receptor antagonist by binding to the IL-36 receptor (IL-36R) and preventing the recruitment of the IL-1 receptor accessory protein (IL-1RAcP). This inhibition blocks the activation of downstream signaling pathways, such as NF-κB and MAPK, which are involved in inflammatory responses . The mouse recombinant IL-36Ra is produced in E. coli and consists of a single, non-glycosylated polypeptide chain containing 154 amino acids, with a molecular mass of 17.0 kDa .
IL-36Ra is normally expressed at low levels but can be induced upon stimulation. It acts on various cells, including epithelial and immune cells, to modulate inflammatory responses. In the skin, IL-36Ra contributes to host defense by regulating the inflammatory response. However, dysregulation of IL-36 signaling can lead to enhanced Th17/Th23 axis activity and induce psoriatic-like skin disorders .
Mutations in the IL-36RN gene, which encodes IL-36Ra, have been associated with several inflammatory skin diseases, including generalized pustular psoriasis, acrodermatitis continua suppurativa Hallopeau (ACH), and acute generalized exanthematous pustulosis (AGEP). These mutations result in a decrease or production of defective IL-36Ra protein, leading to uncontrolled inflammatory responses .
Research on IL-36Ra has shown that anti-IL-36 antibodies can attenuate skin inflammation in mouse models of psoriasis, highlighting its potential as a therapeutic target. The physiological and pathological roles of IL-36 in other organs, such as the lungs, intestines, joints, and brain, are still being investigated .