Interleukin-6 (IL-6) is a proinflammatory cytokine of the IL-6 family, members of which signal through a complex of a cytokine-specific receptor and the signal-transducing subunit gp130. The interaction of IL-6 with the membrane-bound IL-6 receptor (IL-6R) and gp130 stimulates “classic signaling,” whereas the binding of IL-6 and a soluble version of the IL-6R to gp130 stimulates “trans-signaling.” Alternatively, “cluster signaling” occurs when membrane-bound IL-6:IL-6R complexes on transmitter cells activate gp130 receptors on neighboring receiver cells. The soluble form of gp130 (sgp130) is a selective trans-signaling inhibitor, but it does not affect classic signaling. We demonstrated that the interaction of soluble gp130 with natural and synthetic membrane-bound IL-6:IL-6R complexes inhibited IL-6 cluster signaling. Similarly, IL-11 cluster signaling through the IL-11R to gp130 was also inhibited by soluble gp130. However, autocrine classic and trans-signaling was not inhibited by extracellular inhibitors such as sgp130 or gp130 antibodies. Together, our results suggest that autocrine IL-6 signaling may occur intracellularly.

白细胞介素-6（IL-6）是IL-6家族的促炎细胞因子，其成员通过细胞因子特异性受体和信号转导亚基gp130的复合体发出信号。IL-6与膜结合的IL-6受体（IL-6R）和gp130的相互作用刺激了“经典信号传导”，而IL-6和IL-6R的可溶形式与gp130的结合刺激了“反式-信号。” 或者，当发射器细胞上的膜结合IL-6：IL-6R复合物激活相邻接收器细胞上的gp130受体时，发生“簇信号传导”。gp130（sgp130）的可溶形式是选择性的反式信号转导抑制剂，但它不影响经典的信号转导。我们证明了可溶性gp130与天然和合成膜结合的IL-6：IL-6R复合物的相互作用抑制了IL-6簇信号传导。相似地，可溶性gp130也抑制了通过IL-11R向gp130传递的IL-11簇信号。然而，经典的自分泌和反式信号转导不受诸如sgp130或gp130抗体之类的细胞外抑制剂的抑制。在一起，我们的结果表明自分泌IL-6信号可能在细胞内发生。