Study On Relationship Among Helicobacter Pylori Infection , Expression Of PPAR-γ And COX-2 , NF-κB Activation

Background and Aims: Helicobacter pylori(H. pylori) has been affirmed the major pathogenic factor of chronic gastritis, peptic ulcer and correlates with the occurrence of gastric carcinoma closly. Furthermore, this organism was categorized as a class â… carcinogen by International Agency for Research on Cancer. However, the definite mechanisms of pathogenesis and carcinogenesis in H. pylori infection have been unclear. We investigated the expression and regulating mechanisms of correlated gene in gastric mucosal inflammatory reaction induced by H. pylori infection. H. pylori infection followed by the activation of cyclooxygenase-2(COX-2), nuclear transcription factor KappaB(NF-κB) and other cytokine; NF-κB and COX-2 are important agents through the inflammatory reaction. Peroxisome proliferator-activated receptorγ(PPAR-γ) , a receptor belonging to nuclear hormone is dependent on ligand; it can inhibit the secretion of cytokine, suppress inflammatory reaction, regulate the differentiation and proliferation and apoptosis. PPAR-γ, NF-κB and COX-2 have a close relationship, the activation of NF-κB can up-regulate expression of COX-2; 15-Deoxy-â–³^12,14-prostaglandin J₂ ( 15d-PGJ₂ ) forming from COX-2 is the physiological ligand of PPAR-γ; activated PPAR-γcan inhibit inflammatory reaction by inhibiting NF-κB activation . So far the study of relationship between PPAR-γand H. pylori infection is rare, and there have not been systematic study of relationship among PPAR-γ, NF-κB and COX-2 in gastric mucosa of H. pylori-associated disease. We investigated the expression of PPAR-γ,COX-2 and NF-κB activation in H. pylori-associated gastric mucosal lesions and in pre-and post-decade for persistent H. Pylori infection, and analyzed the interaction among H. pylori infection, expression of PPAR-γ,COX-2 and NF-κB activation, in order to elucidate the possible mechanisms of H. pylori infection in the pathogenesis and carcinogenesis. Method : The expression of PPAR-γ,COX-2 and NF-κB activation were detected by two steps immunohistochemical staining in the 209 gastric biopsy specimen from under endoscopic examination. 209 gastric biopsy specimen included: 75 cases of chronic superficial gastritis(CSG)(50 cases H. pylori positive,25 cases H. pylori negative),24 cases of chronic atrophic gastritis(CAG) (13 cases H. pylori positive,11 cases H. pylori negative),90 cases of intestinal metaplasia and dysplasia (45 cases H. pylori positive,45 H. pylori negative) and 20 normal subjects with H. pylori negative for controls. In addition, The expression of PPAR-γ,COX-2 and NF-κB activation were compared between before and after decade for persistent H. Pylori infection in 36 followed patients with CSG. Results:(1)The expression of COX-2 was gradually increased in glandular cells from control group to IM+DYS group, in which CAG group and IM+DYS group were significantly higher than control group(P<0.005-0.05), and IM+DYS group significantly higher than CSG group(P<0.05).Expression of COX-2 of all disease groups were higher than contol group in inflammatory cells, while there was significant difference between IM+DYS and control group(P<0.05), there was no significant difference among various disease groups (P>0.05). (2)In CSG and IM+DYS groups the expression of COX-2 in inflammatory and glandular cells was significantly higher in patients with H. pylori positive than that with H. pylori negative(P<0.05-0.001). The expression of COX-2 in glandular cells was significantly higher in H. pylori positive IM+DYS group than in H. pylori positive CSG group (P<0.05),while there was no significant difference among various diseases groups with H. pylori negative (P>0.05). The expression of COX-2 in inflammatory cells, there was no significant difference each other among various disease groups with H. pylori positive or negative(P>0.05).(3) The expression of NF-κBp65 in glandular cells increased gradually from control group to IM+DYS group, in which IM+DYS group was significantly higher than the others(P<0.001-0.005). The expression of NF-κBp65 in all diseases groups were higher than contol group in inflammatory cells , while there was significant difference between CSG and control group(P<0.05). (4) In inflammatory cells ,the expression of NF-κBp65 in all diseases groups with H. pylori positive were significant higher than all diseases groups with H. pylori negative(P<0.05-0.001),while there was no significant difference each other among various disease groups with H. pylori positive or negative(P>0.05). In glandular cells, The expression of NF-κBp65, there was no significant difference between H. pylori positive and H. pylori negative in various disease (P>0.05). In glandular cells the expression of NF-κBp65 was significant higher in H. pylori positive IM+DYS group than H. pylori positive CSG and CAG group (P<0.05-0.001),and in which expression of NF-κBp65 was significantly higher in H. pylori negative IM+DYS group than in H. pylori negative CSG group (P<0.05). (5) The expression of PPAR-γincreased gradually in glandular cells and inflammatory cells from control group to IM+DYS group, in which IM+DYS group was significantly higher than CSG group (P< 0.0 05), while there was no significant difference each other among various disease groups(P>0.05). (6) In inflammatory cells, the exprssion of PPAR-γwas significantly higher in CSG and IM+DYS groups with H. pylori positive than the same groups with H. pylori negative (P<0.005), while there was no significant difference each other among various disease groups with H. pylori positive or with H. pylori negative(P>0.05). In glandular cells , the expression of PPAR-γwas significantly higher in CSG and IM+DYS groups with H. pylori positive than the same groups with H. pylori negative (P<0.005), and expression of PPAR-γwas significantly higher in H. pylori positive or H. pylori negative IM+DYS groups than H. pylori positive or H. pylori negative CSG groups(P<0.05). (7) In CSG of persistent H. Pylori infection for 10 years, expression of COX-2 was significantly lower after decade than before decade in inflammatory cells(P<0.05). There was no significant difference between before decade and after decade in the expression of NF-κBp65 andPPAR-γin inflammatory cells (P>0.05) (8) In CSG of persistent H. Pylori infection for 10 years, the expression of COX-2 and PPAR-γwas significantly higher after decade than before decade in glandular cells(P<0.01-0.001). There was no significant difference between before decade with after decade in the expression of NF-κBp65 in glandular cells. (9) In inflammatory cells, there were no significant correlation among COX-2 ,PPAR-γand NF-κB in all disease groups with H. pylori negative(P>0.05). In glandular cells, there were significant positive correlation between COX-2 and PPAR-γin IM+DYS group with H. pylori negative(P<0.05); there were no significant correlation among COX-2 ,PPAR-γand NF-κB in CAG and CSG groups with H. pylori negative(P>0.05). (10) In inflammatory cells, there were significant positive correlation among COX-2 ,PPAR-γand NF-κB in all disease groups with H. pylori positive(P<0.05-0.001). In glandular cells, there were significant positive correlation between COX-2 and PPAR-γin all disease groups with H. pylori positive(P<0.05-0.005), and there were no significant correlation between expression of COX-2 ,PPAR-γand NF-κB activation(P>0.05). Conclusion: â‘ H. pylori infection can induce overexpression of COX-2 in inflammatory and glandular cells within gastica mucosa. The overexpression of COX-2 might participate in Hp pathogenicity , and the Hp infection might participate in the earlier period of carcinogenesis by up-regulating the expression of COX-2 protein. â‘¡NF-κB activation induced by H. pylori infection in inflammatory cells within gastica mucosa implies that NF-κB activation participate in inflammatory reaction. The increase of NF-κB activation in glandular cells in gastric precancerous lesion was not influenced by H. pylori infection, it suggests that there are other factors besides H. pylori to induce NF-κB activation and it may participate in the earlier period of carcinogenesis. â‘¢H. pylori infection can induce overexpression of PPAR-γin inflammatory and glandular cells of gastica mucosa, and in glandular cells expression of PPAR-γrelate to the course of gastica mucosa lesion, it suggest overexpression ofPPAR-γmight the earlier event in the course of gastic carcinoma occurrence caused by H. pylori infection. â‘£In CSG of persistent H. Pylori infection for 10 years, the down-regulation of COX-2 exprssion in inflammatory cells implies that expression of COX-2 induced by H. pylori related to acute inflammation caused by H. pylori infection. In glandular cells, significant increase of COX-2 and PPAR-γexpression implies that along with time shift expression of COX-2 and PPAR-γalready changed under the before changeable pathomorphology of gastric mucosa. ⑤The role of expression of COX-2,PPAR-γand activation of NF-κB affects each other in the course of lesion caused by H. pylori infection.