Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by gammadelta and CD4 T cells that mediate autoimmunity.

  • Lalor S
  • Dungan L
  • Sutton C
 et al. 
  • 106

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Abstract

IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1β and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1β and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1β or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1β and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1β and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1β and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.

Author-supplied keywords

  • Animals
  • Autoimmune Diseases
  • Autoimmune Diseases: immunology
  • CD4-Positive T-Lymphocytes
  • CD4-Positive T-Lymphocytes: immunology
  • CD4-Positive T-Lymphocytes: metabolism
  • Carrier Proteins
  • Carrier Proteins: genetics
  • Caspase 1
  • Caspase 1: metabolism
  • Caspase Inhibitors
  • Dendritic Cells
  • Dendritic Cells: immunology
  • Encephalomyelitis, Autoimmune, Experimental
  • Encephalomyelitis, Autoimmune, Experimental: immun
  • Interleukin-17
  • Interleukin-17: biosynthesis
  • Interleukin-17: immunology
  • Interleukin-18
  • Interleukin-18: immunology
  • Interleukin-18: metabolism
  • Interleukin-1beta
  • Interleukin-1beta: immunology
  • Interleukin-1beta: metabolism
  • Interleukin-23
  • Interleukin-23: immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Mycobacterium tuberculosis
  • Mycobacterium tuberculosis: immunology
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Associated Glycoprotein: immunology
  • Myelin-Oligodendrocyte Glycoprotein
  • Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Antigen, T-Cell, gamma-delta: genetics
  • Receptors, Antigen, T-Cell, gamma-delta: immunolog
  • Th17 Cells
  • Th17 Cells: immunology

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Authors

  • Stephen J Lalor

  • Lara S Dungan

  • Caroline E Sutton

  • Sharee A Basdeo

  • Jean M Fletcher

  • Kingston H G Mills

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