Research ArticleCYTOKINES

Homodimerization attenuates the anti-inflammatory activity of interleukin-37

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Science Immunology  10 Feb 2017:
Vol. 2, Issue 8, eaaj1548
DOI: 10.1126/sciimmunol.aaj1548

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Interleukin-37 comes to a head

Although inflammation plays a key role in fighting off infection, uncontrolled inflammatory responses contribute to pathogenesis in diseases ranging from fibrosis to cardiovascular disease to autoimmunity. Interleukin-1 (IL-1) family members as a whole tend to have proinflammatory function; however, IL-37 is something of a black sheep—functioning as a broad-spectrum inhibitor of inflammation. Ellisdon et al. have solved the crystal structure of IL-37 and found that its stable head-to-head homodimer form is less effective than its monomeric form in inhibiting inflammation in both primary human blood cells and a mouse model of endotoxic shock. Hence, an altered IL-37 that exists as a stable monomer would be a prime candidate for anti-inflammatory therapies.


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 β-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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