IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist.
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. Heat-killed 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 (IL-36Ra) 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.
Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA. F.Veerdonk@AIG.umcn.nl
Frank L
FL
van de Veerdonk
Angela K
AK
Stoeckman
Gouping
G
Wu
Aaron N
AN
Boeckermann
Tania
T
Azam
Mihai G
MG
Netea
Leo A B
LA
Joosten
Jos W M
JW
van der Meer
Ruyi
R
Hao
Vassili
V
Kalabokis
Charles A
CA
Dinarello
D000946:Antigens, Fungal / Q000276:immunology; D002176:Candida albicans / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D000097043:Interleukin-22
D000946:Antigens, Fungal; D055767:Immobilized Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D000097043:Interleukin-22; C571243:IL-38 protein, human; C122187:IL36RN protein, human; C571244:interleukin-36 receptor, human