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

Jesse J. Balic, Christoph Garbers, Stefan Rose-John, Liang Yu, Brendan J. Jenkins

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

Deregulated gp130-dependent STAT3 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 IL-11-gp130-STAT3 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 gp130F/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 gp130F/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 gp130F/F mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130F/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 STAT3 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 gp130F/F:Adam17ex/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.

Original languageEnglish
Pages (from-to)118-123
Number of pages6
JournalCytokine
Volume92
DOIs
Publication statusPublished - 1 Apr 2017

Keywords

  • ADAM17
  • Gastric cancer
  • IL-11
  • sgp130Fc
  • STAT3
  • Trans-signalling

Cite this

Balic, Jesse J. ; Garbers, Christoph ; Rose-John, Stefan ; Yu, Liang ; Jenkins, Brendan J. / Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling. In: Cytokine. 2017 ; Vol. 92. pp. 118-123.
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abstract = "Deregulated gp130-dependent STAT3 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 IL-11-gp130-STAT3 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 gp130F/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 gp130F/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 gp130F/F mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130F/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 STAT3 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 gp130F/F:Adam17ex/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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Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling. / Balic, Jesse J.; Garbers, Christoph; Rose-John, Stefan; Yu, Liang; Jenkins, Brendan J.

In: Cytokine, Vol. 92, 01.04.2017, p. 118-123.

Research output: Contribution to journalArticleResearchpeer-review

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