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Apoptosis-induced tolerance. Role of the novel cytokine IL-38

: Mora, J.; Han, Y.; Wittig, I.; Putyrski, M.; Ernst, A.; Brüne, B.; Weigert, A.

Cytokine 87 (2016), pp.109-110
ISSN: 1043-4666
International Cytokine and Interferon Society (ICIS Annual Meeting) <4, 2016, San Francisco/Calif.>
Fraunhofer IME ()

Introduction: Necrotic cell death triggers inflammation, whereas apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction and are produced by necrotic cells to induce sterile inflammation. Release of IL-1 family proteins from apoptotic cells to regulate inflammation has not been described. The novel cytokine IL-38 shares homology with IL-1 family receptor antagonists and was therefore proposed as a negative regulator of IL-1 family receptor signaling.
Methods: IL-38 concentrations were measured by ELISA. Apoptotictumor cell conditioned medium (ACM) was used to stimulate human primary immune cells. The response to ACM was determined as cytokine release (Cytometric Bead Array) as well as transcription factor activity (Luciferase reporter assays). N-terminal processing of IL-38 was determined by mass spectrometry. Binding of IL-38 to its putative receptors was determined by receptor binding assays. The pathophysiological function of IL-38 was analyzed using the imiquimod (IMQ)-induced psoriasis mouse model in IL-38-deficient animals compared to WT controls. Statistical analysis was performed using ANOVA with Bonferroni’s correction.
Results: We show that IL-38 is produced selectively by human apoptotic cells to limit inflammation. Depletion of IL-38 in apoptotic cells provoked enhanced IL-6 and IL-8 levels and AP1 activation in co-cultured human primary macrophages, subsequently inducing IL-17-producing T cell activation. IL-38 was N-terminally processed in apoptotic cells to generate a mature cytokine with distinct properties. Both full-length and truncated IL-38 bound to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1). However, we show higher affinity binding of mature IL-38. Likewise, we confirmed the previously reported low-affinity binding of the IL-38 precursor to IL1R1 and show an increased affinity of mature IL-38 to this receptor. Functionally, the IL-38 precursor induced an increase in IL-6 production by human macrophages, whereas truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. Ongoing studies show selective secretion of IL-38 from dying cells challenged with tolerogenic chemotherapy, but not with immunogenic chemotherapy. Moreover, strengthening the role of IL-38 as a tolerogenic factor, IL-38-deficient mice subjected to IMQ-induced psoriasis show an increased IL-17-mediated immune response and a strong delay in the restoration of skin architecture.
Conclusion: We identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion. IL-38 limits cytokine production in macrophages antagonizing the IL1-RAPL1/JNK/AP1 pathway and subsequently preserving a low T cell IL-17 production. We propose apoptotic cell-derived IL-38 as the counter-regulatory equivalent of necrotic cell-derived alarmins of the IL-1 family, which might be relevant in resolution of inflammation, autoimmunity, and cancer.