The central hypothesis of this research is i) that gastric epithelial hyperplasia Helicobacter pylori infected mice is due to an imbalance, and ii) that this imbalance is mediated by pro-inflammatory cytokines (ie. IFN-gamma, IL-1 and TNF-alpha). This hypothesis is based upon four observations. First, both apoptosis and proliferation are increased in H. pylori-infected mice is dependent on an intact T-cell immune response. Finally, in-vitro data support the proposed relationship between apoptosis, hyperplasia and inflammatory cytokines. Preliminary data have shown that IFN-gamma increases apoptosis in cultured gastric epithelial cells, but conditioned media (which contain IFN-gamma) induce proliferation. Taken together, these data suggests that pre-neoplastic proliferation due to H. pylori is host-mediated, and that both proliferative and apoptotic mechanisms contribute. The initial aim of the study is to confirm the presence and relative quantity of IFN-gamma, IL-1, and TNF-alpha mRNA and protein in gastric tissue and conditioned media from gastric LPL of infected mice.
Aim 2 will evaluate the functional effect of these cytokines on gastric epithelial cell culture and will address the presence and up/down regulation of cytokine receptor mRNA and protein in the cells.
Aim 3 will address apoptosis in chronic H. pylori infection focusing on the Fas and TRAIL mechanisms. Compensatory hyperplasia secondary to the apoptosis will be evaluated.
The final aim will be to evaluate the role of gastric somal and epithelial cells in gastric proliferation.
| Eaton, K A; Logan, S M; Baker, P E et al. (2004) Helicobacter pylori with a truncated lipopolysaccharide O chain fails to induce gastritis in SCID mice injected with splenocytes from wild-type C57BL/6J mice. Infect Immun 72:3925-31 |
| Peterson 2nd, Richard A; Hoepf, Toni; Eaton, Kathryn A (2003) Adoptive transfer of splenocytes in SCID mice implicates CD4+ T cells in apoptosis and epithelial proliferation associated with Helicobacter pylori-induced gastritis. Comp Med 53:498-509 |
