Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses

• Published in: Journal of molecular cell biology 2016-10, Vol.8 (5), p.426-438
• Main Authors: Mora, Javier, Schlemmer, Andrea, Wittig, Ilka, Richter, Florian, Putyrski, Mateusz, Frank, Ann-Christin, Han, Yingying, Jung, Michaela, Ernst, Andreas, Weigert, Andreas, Brüne, Bernhard
• Format: Article
• Language: English
• ISSN: 1674-2788; 1759-4685
• DOI: 10.1093/jmcb/mjw006

Different modes of cell death regulate immunity. Whereas necrotic (necroptotic, pyroptotic) cell death triggers inflammation, apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction. A number of IL-1 family cytokines are produced by necrotic cells to induce sterile inflammation. However, release of IL-1 family proteins from apoptotic cells to regulate inflammation was not described. Here we show that IL-38, a poorly characterized IL-1 family cytokine, 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 Th17 cell expansion at the expense of IL-10-producing T cells. 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, whereas the IL-38 precursor induced an increase in IL-6 production by human macrophages, truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. In conclusion, we identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion, which might be relevant in resolution of inflammation, autoimmunity, and cancer.