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.2012 Feb 21;109(8):3001-5.
doi: 10.1073/pnas.1121534109. Epub 2012 Feb 6.

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

Affiliations

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

Frank L van de Veerdonk et al. Proc Natl Acad Sci U S A..

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. 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
IL-38 inhibitsCandida-induced Th17 cytokine production. Mean ± SEM percent change in supernatant cytokines from human PBMCs exposed toC. albicans in the presence or absence of IL-38 at 100 ng/mL. (A) IL-22 (n = 8). *P < 0.05. (B) IL-17 (n = 6). *P < 0.05. (C) IFN-γ (n = 6).
Fig. 2.
Fig. 2.
Effect of IL-1 and IL-18 blockade on Th17 responses driven byCandida antigen. Mean ± SEM percent change in IL-22 and IL-17 in the supernatant cytokines from human PBMCs exposed toC. albicans in the presence or absence of inhibitors. (A) IL-1Ra at 1,000 ng/mL (n = 8). (B) IL-18BP at 1,000 ng/mL (n = 6). *P < 0.05 using pairedt test.
Fig. 3.
Fig. 3.
IL-36Ra reducesCandida-induced Th17 responses. Mean ± SEM percent change inC. albicans-induced cytokines in the presence or absence of IL-36Ra at 100 ng/mL. (A) IL-22 (n = 10). (B) IL-17 (n = 7). *P < 0.05 using pairedt test.
Fig. 4.
Fig. 4.
Binding curves of IL-38 to immobilized IL-1Rrp2. (A) Flat-bottomed 96-well microtiter plates were coated with 1 μg of the extracellular domain of IL-1 family receptors in 100 μL PBS (Materials and Methods). After blocking with BSA, increasing amounts of IL-38 (shown under the horizontal axis in μg/mL) were added to each well for overnight incubation. Bound IL-38 was detected using biotinylated affinity-purified goat anti–IL-38 antibody, followed by HRP-conjugated streptavidin (n = 3). (B) Comparison of IL-38 and IL-36Ra binding to IL-1Rrp2 (n = 5). The data are expressed as mean ± SD inA and as mean inB.
Fig. 5.
Fig. 5.
IL-38 inhibits IL-36γ–induced IL-8. Percent change (mean ± SEM) in IL-8 from human PBMCs incubated for 24 h with either medium or IL-36γ at 100 ng/mL and in the presence or absence of (A) IL-38 at 10 ng/mL 9 (n = 5) or (B) IL-36Ra at 100 ng/mL (n = 5). *P < 0.05.
Fig. 6.
Fig. 6.
Comparison of the dose–response relationship of IL-38, IL-1Ra, and IL-36Ra onCandida-induced IL-22. Percent change (mean ± SEM) in IL-22 released from PBMCs incubated withC. albicans in the presence or absence of increasing concentrations of (A) IL-38 (n = 4), (B) IL-1Ra (n = 4), and (C) IL-36Ra (n = 4). *P < 0.05.
Fig. 7.
Fig. 7.
IL-38 and IL-36Ra similarly increase LPS-induced IL-6 in DCs. Percent change (mean ± SEM) in human blood monocyte-derived DCs incubated with either medium or LPS (10 ng/mL) in the presence or absence of (A) 100 ng/mL IL-38 (n = 7) or (B) 100 ng/mL IL-36Ra (n = 7). *P < 0.05. LPS induced 1,578 ± 596 pg/mL (mean ± SEM) in DCs.
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