Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling.

Deregulated gp130-dependent signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130(F/F) spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis. sIL-11R protein was detectable in gastric tissue from GC patients, and sIL-11R levels were elevated in tumours of gp130(F/F) mice compared to matched non-tumours. Among candidate proteases associated with the generation of sIL-11R, ADAM10 and the related metalloprotease ADAM17 were significantly upregulated in tumours of both gp130(F/F) mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130(F/F) mice upon the transgenic over-expression of the trans-signalling antagonist, sgp130Fc, failed to suppress gastric inflammation and associated tumour growth, and also had no effect on reducing hyper-activated duanyu18133 levels. Furthermore, a non-essential role for ADAM17 in IL-11-driven gastric tumourigenesis was supported by the observation that the tumour burden was unaffected in gp130(F/F):Adam17(ex/ex) mice in which ADAM17 expression levels have been substantially reduced. Collectively, these findings suggest that classic signalling rather than trans-signalling is the mode by which IL-11 promotes gastric tumourigenesis.

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