Cytokine signalling by gp130 regulates gastric mucosal healing after ulceration and, indirectly, antral tumour progression

The cytokines IL-6 and IL-11, which signal via the receptor gp130, have been implicated in various gut pathologies, including inflammation and wound healing. We used mouse cytokine signalling mutants to evaluate the role of gp130 pathways in gastric ulceration and healing and the effect of spatially remote fundic ulceration on antral tumour progression, since compromised wound healing may impact tumourigenesis. Glacial acetic acid applied to the serosal surface of stomachs from wild-type, gp130(757FF), IL-6(-/-) and IL-11 receptor (R)alpha(-/-) mice was used to induce discrete haemostasis/necrosis and resultant mucosal ulceration. Wound pathology and mRNA expression of key cytokine target genes were examined 2 and 14 weeks after ulcer induction. The outcome of fundic ulceration on antral tumour development in gp130(757FF) mice was also examined. Chemical haemostasis in gp130(7575FF) mice produces more severe gastric ulcers than in wild-type mice. Lack of IL-6 produces more severe ulceration, while loss of IL-11R alpha less severe ulcers, suggesting a role for IL-11 in ulcer induction. Increased expression of ulcer-associated IL-11 and its established mitogenic target genes Reg1, III beta and III gamma paralleled severe ulceration in gp130(757FF) Mice. In this model, coincident with fundic ulceration, antral tumour development was inhibited and correlated with decreased RegI, III beta and III gamma and reduced MMP9 and 13 expression. IL-11-driven transcription via gp130 contributes to the gastric mucosal response to ulceration. Fundic mucosal ulceration modulates antral growth factor and metalloproteinase gene expression, thereby contributing to restricted tumour growth. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.