Homodimerization attenuates the anti-inflammatory activity of interleukin-37
Homodimerization attenuates the anti-inflammatory activity of interleukin-37
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DOI：
10.1126/sciimmunol.aaj1548
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发表时间：
2017-02-01
影响因子：
24.8
通讯作者：
Nold, Marcel F.
中科院分区：
文献类型：
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作者：
Ellisdon, Andrew M.;Nold-Petry, Claudia A.;Nold, Marcel F.
炎症反应的失调是许多疾病的基础。虽然大多数白介素1家族的细胞因子都是促炎因子，但人白介素37(IL-37)是一种有效的、广谱的炎症和免疫抑制因子。我们测定了IL-37的晶体结构，以期为开发基于IL-37的治疗药物奠定基础。我们发现，两个β-三叶折叠的IL-37分子形成了在溶液中稳定的头对头二聚体。IL-37突变体将细胞因子转化为专性单体，在抑制原代人类血细胞和小鼠内毒素休克体内的促炎事件方面，其效果比二聚体高达13倍。对单体IL-37强大抗炎特性的治疗性开发可能有助于治疗广泛的炎症性和自身免疫性疾病。
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.