title: Molecular determinants of agonist and antagonist signaling through the IL-36 receptor.
abstract: The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Günther
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201 esundberg@ihv.umaryland.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sundberg
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
chemical_list: D007375:Interleukin-1; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C572887:interleukin 36, human; C571244:interleukin-36 receptor, human