S1654 Pro-Inflammatory Cytokines Regulate IL-1 Receptor 1(IL-1R1)/IL-1 Receptor Accessory Protein (IL-1racp) Signaling Through p38 MAPK to Decrease Gastric Barrier Function in Helicobacter pylori Infection

Abstract

genes in mice (Hsp70.1 and Hsp70.3), where 11-kb of genomic DNA separating the 5' end of Hsp70.3 and the 3' end of Hsp70.1 was replaced with a 3.1-kb neo gene driven by the RNA polymerase II gene promoter. Infection of male and female mice was done using SS1 HP. Tissues were collected at 17, 24, and 34 weeks post infection (wkPI) and evaluated for histopathology changes. To determine levels of HSP70 protein expression, immunostaining for HSP70 was done in KO and HSP70+/+ mice. Results: HSP70 protein expression in HPinfected HSP70+/+ mice was induced to high levels from 6-12 wkPI after which the expression was attenuated significantly. The induced expression of HSP70 localized most strongly to tight junctions in surface epithelial cells while no induced expression occurred in KO mice. In KO mice, the histopathology grade for inflammation, hyperplasia, oxyntic atrophy, pseudopyloric metaplasia, and epithelial defects showed a strong gender response that was significantly more robust in female compared to male mice and in all categories the pathological changes were significantly greater in HP-infected compared to uninfected mice. The most significant finding was that gastric epithelial dysplasia, which in female mice occurred by 17 wkPI, was present in both genders by 34 wkPI. The histopathology grade for dysplasia was significantly greater (P<0.001) in female compared to male mice at 34 wkPI (1.667 ± 0.168 in female vs 0.4 ± 0.208 in male) and was significantly greater (P<0.001) in female HP-infected compared to uninfected mice. In HP-infected KO mice, gastric surface cells appeared disrupted and numerous scars were present along the apical surface, suggesting damage occurs to the gastric mucosal barrier in the absence of HSP70. Conclusions: Deletion of HSP70 during HP infection leads to early dysplasia of the gastric corpus that is associated with damage to surface epithelial cells. These results demonstrate that HSP70 is an important host factor that protects against gastric cancer development in mice.