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Abstract

About 20 years ago, several organisations looking for genes with sequence homology to the cytokine family IL-1 found the IL-36 cytokines. One of these investigations, written up in 2001 by Debets and colleagues, showed that human keratinocytes expressed IL-1 and IL-1, now known as IL-36 and the IL-36R antagonist (IL-36Ra), respectively. This was especially true after stimulation with IL-1 and TNF. Three pro-inflammatory cytokines from the IL-36 family—IL-36, IL-36, and IL-36—as well as a receptor antagonist—IL-36Ra—bind to and signal through a heterodimeric receptor made up of IL-36R and the IL-1R accessory protein (IL-1RAcP). A result that directly connects dysregulated IL-36 pathway activation to inflammatory skin disorders is the development of generalised pustular psoriasis in people with inactivating mutations in the gene for IL-36Ra, a severe type of psoriasis. This review’s focus is on the cellular origins of IL-36 cytokines, the effects of IL-36 signalling on different cell types, and the relationship between IL-36 and a range of inflammatory skin conditions, such as different types of psoriasis, hidradenitis suppurativa, atopic dermatitis, and allergic contact dermatitis.