Interleukin-36

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, around 38 different interleukins have been clearly identified. Each cytokine in the interleukin group is assigned a nomenclatural number for its classification (IL-1 to IL-38 - as of 2017).

Interleukin-36 alpha, IL-36beta, IL-36gamma and IL-36Ra are members of the interleukin-1 family that bind to a common receptor, the interleukin-36 receptor. All 4 interleukin-36 subunits are encoded by different genes.

The common interleukin-36 receptor is composed of 2 chains: IL-36R and IL-1R/AcP. The cytokine-receptor complex bound by interleukin-36alpha, IL-36beta and IL-36gamma activates NF-kappaB and MAPKs and induces inflammatory responses via these signals.

The receptor protein IL-36Ra (encoded by the IL36RN gene ), an IL-36 receptor antagonist, is also a member of the interleukin-1 cytokine family. This receptor protein is mainly found in the skin and is a natural antagonist of the three IL-36 agonists interleukin-36alpha, IL-36beta and IL-36gamma. Interleukin-36Ra also binds to the interleukin-36 receptor, thus inhibiting the binding of the agonistic ligands to this receptor.

The cytokines of the interleukin-36 group are predominantly expressed by epithelial cells. They act on immune cells, activating dendritic cells in particular; they also influence epithelial cells and fibroblasts.

The role of interleukin-36 has mainly been demonstrated in the skin. Interleukin-36 cytokines can trigger inflammatory reactions via induction in keratinocytes. They are involved in psoriatic inflammation.

A mutation of the gene coding for the interleukin receptor antagonist interleukin-36Ra(IL36RN) leads to an aberrant function of this receptor cytokine, to an unregulated production of inflammatory cytokines, and clinically to severe generalized pustular psoriasis (Marrakchi S et al. 2011).

In primary Sjögren's sydrome, elevated serum and tissue levels of IL-36alpha are found. An anti-interleukin-36 antibody(spesolimab - approval has since been withdrawn) was approved for generalized pustular psoriasis.

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