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-11Ralpha 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 RegI, IIIbeta and IIIgamma paralleled severe ulceration in gp130(757FF) mice. In this model, coincident with fundic ulceration, antral tumour development was inhibited and correlated with decreased RegI, IIIbeta and IIIgamma 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.
Judd
Louise M
LM
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia. lmj@unimelb.edu.au
Ulaganathan
Meera
M
Howlett
Meegan
M
Giraud
Andrew S
AS
D019342:Acetic Acid; D000818:Animals; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D018450:Disease Progression; D005355:Fibrosis; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000276:immunology*
D017370:Interleukin-11; D015850:Interleukin-6; D050822:Cytokine Receptor gp130; D019342:Acetic Acid