Journal
SCIENCE IMMUNOLOGY
Volume 2, Issue 8, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aaj1548
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Funding
- National Health and Medical Research Council of Australia (NHMRC) Project [1012353, 1043845]
- Monash University Strategic Grant [ECD0039]
- Future Leader Fellowship by the National Heart Foundation of Australia
- Paul Korner Award by the National Heart Foundation of Australia
- Larkins Fellowship by Monash University
- Star Recruitment Fellowship by the Hudson Institute of Medical Research
- Ritchie Centre's Victor Yu Fellowship
- Fielding Innovation Award by the Fielding Foundation
- Fielding Innovation Fellowship by the Fielding Foundation
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Dysregulation of the inflammatory response underlies numerous diseases. Although most interleukin-1 family cytokines are proinflammatory, human interleukin-37 (IL-37) is a powerful, broad-spectrum inhibitor of inflammation and immunity. We determined the crystal structure of IL-37 to establish the anti-inflammatory mechanism of this key cytokine in view of developing IL-37-based therapies. We found that two beta-trefoil fold IL-37 molecules form a head-to-head dimer that is stable in solution. IL-37 variants mutated to convert the cytokine into an obligate monomer were up to 13-fold more effective than the dimer in suppressing proinflammatory events both in primary human blood cells and in vivo in murine endotoxic shock. Therapeutic exploitation of the powerful anti-inflammatory properties of monomeric IL-37 may prove beneficial in treating a wide range of inflammatory and autoimmune disorders.
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