Interleukin-36 Gamma (IL-36γ) is a member of the interleukin-1 (IL-1) superfamily, which includes a variety of cytokines involved in inflammatory and immune responses. IL-36γ, along with IL-36α and IL-36β, functions as an agonist, while IL-36Ra acts as an antagonist . These cytokines play crucial roles in modulating the immune system and are implicated in various inflammatory diseases.
IL-36γ is a protein encoded by the IL36G gene located on human chromosome 2 . The IL-36 family members share structural similarities with other IL-1 cytokines, including a conserved β-trefoil fold. IL-36γ binds to the IL-36 receptor (IL-36R), which is a heterodimer composed of IL-1 receptor-related protein 2 (IL-1Rrp2) and the IL-1 receptor accessory protein (IL-1RAcP) . Upon binding to IL-36R, IL-36γ activates downstream signaling pathways, including the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways .
IL-36γ is primarily expressed in epithelial cells, keratinocytes, and various immune cells . It plays a significant role in the regulation of immune responses, particularly in the skin, lungs, and gastrointestinal tract. IL-36γ is involved in the activation of immune cells, antigen presentation, and the production of pro-inflammatory cytokines and chemokines . It contributes to host defense mechanisms by promoting inflammation and enhancing the immune response.
Dysregulation of IL-36γ has been associated with several inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease . In psoriasis, IL-36γ stimulates keratinocytes and immune cells, leading to the activation of the Th17/Th23 axis and the development of psoriatic lesions . Genetic mutations in the IL36RN gene, which encodes the IL-36Ra antagonist, are linked to generalized pustular psoriasis, a severe and life-threatening form of the disease .
Given its role in inflammatory diseases, IL-36γ has emerged as a potential therapeutic target. Anti-IL-36 antibodies have shown promise in preclinical studies, where they attenuated skin inflammation in mouse models of psoriasis . Further research is needed to explore the therapeutic potential of targeting IL-36γ in other inflammatory conditions.