IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist

Abstract

The functional role of IL-1 family member 10, recently renamed IL-38, remains unknown. In the present study we aimed to elucidate the biological function of IL-38 and to identify its receptor. Heatkilled Candida albicans was used to stimulate memory T-lymphocyte cytokine production in freshly obtained human peripheral blood mononuclear cells from healthy subjects. The addition of recombinant IL-38 (152 amino acids) inhibited the production of T-cell cytokines IL-22 (37% decrease) and IL-17 (39% decrease). The reduction in IL-22 and IL-17 caused by IL-38 was similar to that caused by the naturally occurring IL-36 receptor antagonist (IL36Ra) in the same peripheral blood mononuclear cells cultures. IL-8 production induced by IL-36γ was reduced by IL-38 (42% decrease) and also was reduced by IL-36Ra (73% decrease). When human blood monocyte-derived dendritic cells were used, IL-38 as well as IL-36Ra increased LPS-induced IL-6 by twofold. We screened immobilized extracellular domains of each member of the IL-1 receptor family, including the IL-36 receptor (also known as "IL-1 receptor-related protein 2") and observed that IL-38 bound only to the IL-36 receptor, as did IL-36Ra. The dose-response suppression of IL-38 as well as that of IL-36Ra of Candida-induced IL-22 and IL-17 was not that of the classic IL-1 receptor antagonist (anakinra), because low concentrations were optimal for inhibiting IL-22 production, whereas higher concentrations modestly increased IL-22. These data provide evidence that IL-38 binds to the IL-36R, as does IL-36Ra, and that IL-38 and IL-36Ra have similar biological effects on immune cells by engaging the IL-36 receptor.

Interleukin-36α axis is modulated in patients with primary Sjögren's syndrome

“…The immune effects of IL-36a seem to be antagonized by two different IL-36R ligands, IL-36RA and IL-38. Ligation of IL-36RA and/or of IL-38 with the IL-36R may, in fact, reverse the proinflammatory properties of IL-36a [21].…”

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

“…Thus, in vitro, IL-38 inhibits the production of Th1 cytokines, IL-17, and IL-22. IL-38, similarly to IL-36Ra, has an anti-inflammatory effect on PBMCs, contrasting with a clearly pro-inflammatory effect on DC with increased IL-6 production [45]. IL-38 is selectively secreted by human apoptotic cells to counteract inflammation.…”

IL-36 Receptor Antagonist with Special Emphasis on IL-38

“…During the past several years many papers have described a key role for IL-36 in psoriasis which is overexpressed in the skin of human plaque psoriasis (17)(18)(19). The inhibition of IL-36 with IL-36RA in human psoriatic skin has been found to ameliorate the inflammatory reactions (20)(21)(22)(23). It has been shown that IL-22, IL-17A, and TNF-a induce the ex vivo production of all three IL-36 by human keratinocytes, whereas IFN-y selectively induces IL-36P (24-26).…”