title: Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses.
abstract: 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.
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.|Faculty of Microbiology, University of Costa Rica, 2060 San José, Costa Rica.
authors.forename: Javier
authors.initials: J
authors.lastname: Mora
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlemmer
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.|Cluster of Excellence 'Macromolecular Complexes', Goethe University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Richter
authors.affiliation: Institute of Biochemistry II, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Putyrski
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Frank
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.|Faculty of Veterinary Medicine, Jilin University, 130062 Changchun, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Biochemistry II, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ernst
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
keywords: IL-1 family; apoptosis; cancer; inflammation