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The IL-36 subfamily of cytokines is the most diverse, including three agonists(IL-36α, IL-36β, and IL-36Γ), one antagonist(IL-36Ra), one cognate receptor(IL-36R) and one accessory protein(IL-1RAcP). The receptor activation follows a two-step mechanism in that the agonist first binds to IL-36R and the resulting binary complex recruits IL-1RAcP. IL-36γ that binds to and signals through the IL-36R which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health.