Interleukin-11 (IL-11) and IL-6 are secreted glycoproteins which fulfill important homeostatic functions. Activation of target cells occurs via membrane-bound IL-11 and IL-6 receptors (IL-11R and IL-6R, respectively). Formation of IL-11/IL-11R and IL-6/IL-6R complexes triggers the recruitment of a homodimer of the ubiquitously expressed signal-transducing β-receptor gp130 (classic signaling). IL-11R and IL-6R can be shed by several proteases, albeit with different preferences and specificities, and these soluble receptors (sIL-11R and sIL-6R) act as agonists and can activate in principle all cells via gp130. We have termed these protease-controlled pathways IL-6 and IL-11 trans-signaling. In this review, we describe the basic biology of both cytokines and summarize the current knowledge how proteases control and shape the trans-signaling pathways of the two cytokines. We will further highlight how the underlying molecular mechanisms can be used to design specific inhibitors that block trans, but not classic signaling of IL-11 and IL-6. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
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