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Germ-Line p53-targeted Disruption Inhibits Helicobacter-induced Premalignant Lesions and Invasive Gastric Carcinoma through Down-Regulation of Th1 Proinflammatory Responses¹

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [J. G. F., B. J. S., C. A. D., M. T. W., M. I.], and University of Massachusetts Medical Center, Worcester, Massachusetts 01605 [T. C. W.]

p53 is a tumor suppressor gene that is mutated in many human malignancies, including gastric cancer. It remains unclear why patients with germ-line p53 mutations (i.e., Li-Fraumeni syndrome) are not at increased risk for gastric adenocarcinoma, despite the fact that they show a high rate of many other tumors. Furthermore, the precise relationship between germ-line p53 mutations and the response to chronic bacterial infections (such as Helicobacter spp.) has not been investigated. To assess the role of germ-line p53 deletions in modulating the progression to gastric cancer, p53^+/- and wild-type (WT) C57BL/6 mice were infected with H. felis. The gastric pathology and immune response in these two groups of mice were analyzed for up to 15 months postinfection. The gastric fundus and antrum were evaluated independently using a 0–4 scale to score inflammation, parietal and chief cell loss, mucus metaplasia, and helicobacter colonization. Nonparametric statistical analysis was performed to determine the effects of p53^+/-, infection status, and postinoculation (p.i.) time on inflammation, preneoplastic changes, invasive lesions, and helicobacter colonization. mRNA expression for IFN, interleukin (IL)-1, IL-10, and IL-4 was quantified by PCR. Sera were also evaluated for H. felis antibody by ELISA. Antral inflammation increased significantly with time in infected mice. There was a significant, protective effect on the development of preneoplastic fundic lesions and invasive carcinoma attributable to the deletion of one p53 allele (P < 0.05). Submucosal invasive foci were observed in 9 of 11 WT-infected mice ranging from 13 to 15 months p.i.; invasion of adjacent submucosal blood vessels by glandular epithelia also was present in 5 of these mice. None of these lesions were observed in 33 p53^+/- mice, infected or not, at any time p.i. p53^+/- mice had significantly higher helicobacter colonization consistent with a Th2 host response. In sera from WT mice, IgG2a, considered a proinflammatory Th1 response, continued to rise throughout the 15-month study (P < 0.004). In contrast, IgG2a levels of the p53^+/- mice were 50–60% lower than those of the WT mice at each time point (P range, <0.012 to 0.002) and did not progress in magnitude between 12 and 15 months of chronic H. felis infection (P = 0.167). mRNA levels for IFN and IL-1 were significantly up-regulated in WT mice infected with H. felis (P < 0.05) but were slightly elevated or were at background levels in p53^+/- mice. IL-10 and IL-4 mRNA expression was not significantly different from control samples. Our results support the hypothesis that germ-line deletion of one p53 allele results in a down-regulated Th1 response to gastric helicobacter infection, possibly because of T-cell senescence, which may indirectly protect against the development of gastric cancer and other epithelial-derived neoplasms associated with chronic inflammation.

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