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.

Background:In the classical pathway of the complement system, activated C1s cleaves C4. Results: C4 binding parameters and the crystal structure of CCP1-CCP2-SP of C1s zymogen are reported. Conclusion: C1s must be activated, with repositioning of two loops in its SP domain, before it can bind C4. Significance: Even when the SP of C1s zymogen is exposed, it cannot bind C4.

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