IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction

Nat Immunol. 2015 Apr;16(4):354-65. doi: 10.1038/ni.3103. Epub 2015 Mar 2.

Abstract

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology*
  • Interleukin-18 Receptor alpha Subunit / antagonists & inhibitors
  • Interleukin-18 Receptor alpha Subunit / genetics
  • Interleukin-18 Receptor alpha Subunit / immunology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / pathology
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / immunology
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins c-fyn / genetics
  • Proto-Oncogene Proteins c-fyn / immunology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / deficiency
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • Signal Transduction / immunology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology
  • c-Mer Tyrosine Kinase

Substances

  • IL37 protein, human
  • Interleukin-1
  • Interleukin-18 Receptor alpha Subunit
  • Lipopolysaccharides
  • NF-kappa B
  • P62 protein, human
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, Interleukin-1
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TIR8 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase
  • FYN protein, human
  • Proto-Oncogene Proteins c-fyn
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • PTEN Phosphohydrolase
  • PTEN protein, human

Associated data

  • SRA/SRP051714