Interleukin-6 (IL-6) is a multifaceted cytokine essential in many immune system processes and their regulation. It also plays a key role in hematopoiesis, and in triggering the acute phase reaction. IL-6 overproduction is critical in chronic inflammation associated with autoimmune diseases like rheumatoid arthritis and contributes to cytokine storms in COVID-19 patients. Over 20 years ago, researchers proposed that IL-6, which is typically monomeric, can also form dimers via a domain-swap mechanism, with indirect evidence supporting their existence. The physiological significance of IL-6 dimers was shown in B-cell chronic lymphocytic leukemia. However, no structures have been reported so far. Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.

中文翻译：

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IL-6 结构域交换二聚体抑制信号复合物的结构基础


白细胞介素 6 （IL-6） 是一种多方面细胞因子，在许多免疫系统过程及其调节中必不可少。它还在造血和触发急性期反应中起关键作用。IL-6 过量产生在与类风湿性关节炎等自身免疫性疾病相关的慢性炎症中至关重要，并导致 COVID-19 患者的细胞因子风暴。20 多年前，研究人员提出 IL-6 通常是单体的，也可以通过结构域交换机制形成二聚体，有间接证据支持它们的存在。IL-6 二聚体的生理意义在 B 细胞慢性淋巴细胞白血病中表现出来。然而，到目前为止还没有任何结构的报道。在这里，我们展示了计算方法无法预测的 IL-6 结构域交换二聚体的晶体结构。该结构解释了为什么 IL-6 二聚体在信号复合物形成中与 IL-6 单体拮抗，并为 IL-6 靶向治疗提供了见解。