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Caspase-1-Processed Cytokines IL-1 beta and IL-18 Promote IL-17 Production by gamma delta and CD4 T Cells That Mediate Autoimmunity

The Journal of immunology (1950), 2011-05, Vol.186 (10), p.5738-5748 [Peer Reviewed Journal]

ISSN: 0022-1767 ;EISSN: 1550-6606 ;DOI: 10.4049/jimmunol.1003597

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  • Title:
    Caspase-1-Processed Cytokines IL-1 beta and IL-18 Promote IL-17 Production by gamma delta and CD4 T Cells That Mediate Autoimmunity
  • Author: Lalor, Stephen J ; Dungan, Lara S ; Sutton, Caroline E ; Basdeo, Sharee A ; Fletcher, Jean M ; Mills, Kingston HG
  • Subjects: Mycobacterium tuberculosis
  • Is Part Of: The Journal of immunology (1950), 2011-05, Vol.186 (10), p.5738-5748
  • Description: IL-1 beta plays a critical role in promoting IL-17 production by gamma delta 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-1 beta 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-1 beta 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-1 beta or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and gamma delta T cells in vivo and attenuated the clinical signs of EAE. gamma delta T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1 beta and IL-23, stimulated IL-17 production by gamma delta T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1 beta 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-1 beta and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.
  • Language: English
  • Identifier: ISSN: 0022-1767
    EISSN: 1550-6606
    DOI: 10.4049/jimmunol.1003597
  • Source: Geneva Foundation Free Medical Journals at publisher websites
    Alma/SFX Local Collection
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