Research ArticleCytokines

Soluble gp130 prevents interleukin-6 and interleukin-11 cluster signaling but not intracellular autocrine responses

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Sci. Signal.  02 Oct 2018:
Vol. 11, Issue 550, eaar7388
DOI: 10.1126/scisignal.aar7388

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Inside IL-6 inflammation

Members of the interleukin-6 (IL-6) family of proinflammatory cytokines, which includes IL-6 and IL-11, stimulate responses by binding to a complex of their cytokine-specific receptor and the gp130 signaling receptor. Both of these receptor subunits can be shed from the cell surface and regulate distinct mechanisms of gp130-mediated signaling. Lamertz et al. engineered a reductionist system to interrogate how cells respond to wild-type and synthetic IL-6 and IL-11 cytokines. The authors found that a soluble form of gp130 blocked responses to IL-6 and IL-11 that were presented in trans by a neighboring cell. In contrast, extracellular blockade of cell surface gp130 had no effect on the response to autocrine IL-6, suggesting that these responses could occur within the cell.

Abstract

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.

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