The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease

Nat Immunol. 2007 Mar;8(3):247-56. doi: 10.1038/ni1439. Epub 2007 Feb 4.

Abstract

T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adoptive Transfer
  • Animals
  • Autoimmune Diseases*
  • Autoimmunity
  • B-Cell Activation Factor Receptor / immunology
  • B-Cell Activation Factor Receptor / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / pathology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression
  • Gene Expression Regulation / immunology
  • HeLa Cells
  • Humans
  • Inflammation / immunology*
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Mice
  • Receptors, Interleukin-17 / immunology
  • Receptors, Interleukin-17 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • Transfection
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell Activation Factor Receptor
  • CD40 Antigens
  • IL17RA protein, human
  • Interleukin-17
  • Receptors, Interleukin-17
  • TRAF3IP2 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins