Influential cytokines in the normal gastric mucosa, Helicobacter pylori infection and gastric cancer

© 2014 Dr. Jon-Nicholas BuzzelliGastric cancer is an inflammatory based disease most commonly caused by chronic H. pylori infection. Recent studies have identified two pleiotropic cytokine families, IL-1 and IL-6, to be involved in the progression of gastric cancer. IL-6 cytokines signal via the gp130 complex and predominantly activate MAPK/ERK and JAK/STAT3. The IL-6 cytokine, IL-11, is progressively increased from chronic H. pylori infection to gastric carcinoma and is indispensable in the gp130757FF mouse model of gastric cancer. In addition, administration of exogenous IL-11 to mice has recently been demonstrated to induce gastritis. Although these findings suggest IL-11 is associated with advanced gastric disease, the capacity of IL-11 to induce severe gastric pathology has not been investigated. This body of work assesses whether IL-11 can induce advanced gastric pathology and the mechanism in which it may do so. In addition, the importance of IL-1 signalling in IL-11/STAT3 mediated gastric pathology is investigated and the function of an IL-11 signalling target, IL-33, is characterised in the stomach. To determine whether IL-11 can promote advanced stages of gastric cancer progression, a transgenic mouse model was created to specifically overexpress IL-11 in the stomach. Gastric pathology incidence was low (22%), however overexpression of IL-11 in conjugation with short-term H. pylori-SS1 infection caused a substantial increase in pathology incidence (64%) and pathology was consistent with low grade dysplasia. Overexpression of IL-11 caused an increase in gastric growth factors and innate inflammatory genes at the expense of gastric homeostatic genes. In addition, K19-IL11HIGH mice had increased populations of gastric dendritic cells and a decline in B220INT/CD4+ cells as well as a splenic increase in myeloid cell populations prior to H. pylori infection. This shift in gastric immunity in conjugation with increased growth factors is the most likely cause of gastric pathology. IL-1 signalling is a major component of H. pylori-induced gastric cancer. To dissect the contribution of IL-1 signalling in IL-11/STAT3 mediated gastric cancer, IL-ILRT1-/- mice were crossed to gp130757FF mice and aged to 12 weeks. Surprisingly, gp130757FFxIL-ILRT1-/- mice presented with an increase in antral tumour size compared to gp130757FF mice. gp130757FFxIL-ILRT1-/- mice also had a large increase in the incidence and size of cardiac lesions. gp130757FFxIL-ILRT1-/- cardiac lesions were associated with increased mRNA expression of MDSC markers, including TNF-, and the loss of TNF- in gp130757FF mice reduced tumour burden suggesting MDSCs may drive cardiac pathology. Systemic administration of IL-11 also induced splenic MDSC expansion. These data suggest that IL-1 is not required for IL-11/STAT3 mediated gastric pathology, and in fact, the loss of IL-1 may promote IL-11/STAT3 pathology. In addition, these data suggest IL-11 can induce cardiac pathology which may have implications for Barrett’s Esophagusand oesophageal cancer. Finally, the function of IL-33 in the stomach was defined. IL-33 is a novel alarmin and promotes Th2 immunity. In the stomach, IL-33 expression was localised to the nucleus of SMCs. In keeping with an alarmin function, IL-33 was responsive to bacterial load and insult, and its expression was increased acutely following H. pylori infection. However, IL-33 expression was decreased during chronic H. pylori infection. This may be a key event in establishing Th1/ Th17 biased inflammation in this disease. I have also demonstrated that IL-33 is regulated by TFF2 and activates ILC2s. In the stomach, chronic IL-33 treatment caused Th2/STAT3-mediated gastric pathology, which was most pronounced in the fundus and cardia. This pathology is dependent of lymphocyte migration. Collectively, this study highlights the requirement for stringent regulation of gastric inflammation. Furthermore, it demonstrates that IL-11 directly induces advanced gastric pathology, independent of IL-1 signalling whilst one IL-11 regulated gene, IL-33, may be essential for maintaining balanced immunity in the gastric mucosa