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Su1933 Investigating the Role of Helicobacter pylori Pria Protein
AGA Abstracts
suppresses the development of MGC. To clarify the molecular changes due to H. pylori eradication, in this study, we evaluated differences in molecular alterations related to carcinogenesis in background mucosa of GC between H. pylori positive and negative patients. Materials and Methods: Seventy-seven consecutive patients who underwent ER for GC were enrolled. H. pylori status was analyzed in each patient by two methods: Giemsa staining and serum H. pylori-IgG antibody. Biopsy specimens were obtained from all cases, and DNA was extracted from intestinal metaplasia (IM), a precancerous lesion, via laser capture microdissection. Microsatellite instability (MSI) was evaluated at five loci based on the Bethesda panel; promoter methylation at hMLH1, E-cadherin, p16, and APC was assessed using methylation-specific polymerase chain reaction. Reactivity of monoclonal antibody for colonic phenotype (mAb Das-1) to IM was also evaluated by an immunoperoxidase assay. Results: H. pylori status was negative in 32 of 77 participants (41.6%). The incidence of MSI and hypermethylation at hMLH1, E-cadherin, p16, and APC genes in IM for H. pylori positive and negative patients, respectively, were 47.6%, 23.7%, 10.5% and 56.1% and 36.7%, 6.7%, 3.4%, 38.7% and 35.5%. There were no significant differences in molecular alterations between H. pylori positive and negative cases. mAb Das-1 reactivity to IM was 70.5% in H. pylori positive and 71.0% in H. pylori negative patients, demonstrating no significant difference. Conclusions: Early GC occurs frequently even in H. pylori negative patients. There were no significant differences in molecular alterations in IM between H. pylori positive and negative patients, suggesting that H. pylori eradication may not change the course of molecular alterations in background mucosa once GC has occured in the stomach.
Su1933 Investigating the Role of Helicobacter pylori Pria Protein Aparna Singh, Dusan Blaskovic, Jungsoo Joo, Ming Yan, William G. Coleman Background: In bacteria, PriA protein, a conserved DEXH-type DNA helicase, plays a central role in replication restart at stalled replication forks. Its unique DNA binding property allows it to recognize and stabilize stalled forks and the structures derived from them. PriA plays a very critical role in replication fork stabilization and DNA repair in E. coli and N. gonorrhoeae. In our in vivo expression technology screen, priA gene was induced in vivo when Helicobacter pylori (H. pylori) infects mouse stomach. We decided to elucidate its role in H. pylori infections. Methods: priA gene null mutation was generated by insertion mutagenesis. Kanamycin gene along with its own promoter was inserted at nucleotide 435 of priA gene. The resulting plasmid, ppriA::Kan, was used to transform H. pylori strain SS1 strain by electroporation and natural transformation. Kanamycin-resistant transformants for priA disruption in H. pylori SS1 were verified by PCR analysis. The strain was named as priAKO. We also generated a priA gene complemented strain which contains pHel2 shuttle plasmid construct containing priA gene along with its own promoter. This strain was named as priAKOComp. We did a comparative analysis of WT HpSS1, priA null mutant (priA KO) and priA gene complemented (priAKOComp) strains by inducing mice infections with all three strains. Mice stomachs were harvested at 4 weeks and 8 weeks of infection to determine the colonization levels. Further experiments were also done with these three strains to monitor the growth rate, analyze sensitivity to acid stress, analyze the DNA repair capability and determine the sensitivity to oxidative damage. Results: We observed that the WT HpSS1 strain could colonize mice very well, priAKO strain was unable to colonize mice and the priAKO Comp strain was able to restore the colonization ability. However, the colonization ability of priAKO Comp strain was lower than wild type HpSS1. in-vitro experiments have demonstrated that priAKO strain grows slowly for the first eight hours and after that the growth rate is comparable to wild type strain. priAKO strain has less survival in acidic medium and is also more sensitive to DNA damaging agents as compared to the wild type strain. Conclusion: These data suggest that PriA protein is needed for survival during mice stomach colonization. Ongoing experiments in our laboratory will provide more insight in determining the role of PriA protein in survival and colonization of H. pylori.
Su1931 Genetic and Serological Predictors of H. pylori Infection in Patients With Inflammatory Bowel Disease Brian L. Huang, Jaimin Amin, Michael J. Stewart, Xiaofei Yan, Jessica L. Yoon, Gil Y. Melmed, Andrew Ippoliti, Eric A. Vasiliauskas, Puja Khanna, Marla Dubinsky, Phillip Fleshner, Yodit Alemayehu, Stephan Targan, Dermot P. McGovern, David Q. Shih Background: H. pylori (HP) cause several gastric mucosal diseases including chronic gastritis, PUD, MALT lymphoma, and gastric cancer. Previous studies showed a genetic association between HP infection and an IBD risk SNP ATG16L1 T300A. Other genetic and serological variations on HP infection in IBD is not known. Aim: Identify genetic and serological factors associated with susceptibility to HP infection among IBD patients. Methods: This case control study compared characteristics between non-Hispanic Caucasian IBD patients with documented HP infection (HP+, n=42) by serology, stool antigen test, urease test, or IHC staining to those without HP infection (HP-, n=556). Genetic and serological information were available in all 556 HP- controls and 30 HP+ (after quality control) cases. Logistic regression tests for association with HP infection were performed using the immunochip after correction for population structure with PCA. ≥100,000 Permutations were performed on significant results. Nominal level for genome-wide association was defined as a permuted p>5E05 and association at known IBD SNPs was considered significant with a permuted p>0.05. Association between IBD serology (ASCA, OmpC, I2, p-ANCA, and CBir-1) and HP infection were performed. Results: HP infection was present in 42 of 598 (7%) IBD patients (HP prevalence in non-Hispanic Caucasian in US is approximately 26%). Five loci encoding a total of 6 genes were associated with HP infection in IBD patients at a level consistent with nominal association at the genome-wide level (p<0.00005) including: rs6046489 (Ras interaction-interference proteins, RIN2), rs17188857 (zinc finger protein ZNF521, chromosome translocation protein SS18), rs140226558 (ribosomal protein ANL3), rs72781747 (Protein kinase C theta type, PRKCQ), rs16829789 (GTPase-activating protein, CDGAP). Additionally, 4 previously identified IBD-associated SNP in the IL27 (rs26528), SMAD7 (rs7240004), TRIB1 (rs921720), and the NOD2 frameshift (rs574329 - NOD2fsinsC) were also associated with HP infection in IBD with p<0.05. The previously identified IBD associated ATG16L1 T300A SNP was not associated with HP infection in our IBD patients. Of the IBD serologies, HP infection in IBD is associated with elevated levels of I2 (mean increase of 12 EU, p=0.03). Discussion: Additional 5 genetic loci with nominal association at the genome wide level and 3 known IBD associated loci that are associated with HP infection in IBD patients were identified. These genetic loci are grouped in genes involved in immune regulation (ZNF521, PRKCQ, IL12, SMAD7, NOD2) and oncogenic process (ANL3, RIN2, CDGAP, SS18, SMAD7). The level of I2 serology is elevated in IBD patients with HP infection. Our data suggest that altered bacteria sensing may lead to immune and oncogenic pathways involved in HP associated gastric disease.
Su1934 Loss of Notch1 Function in Helicobacter pylori Contributes to Gastric Mucosal Atrophy and Carcinogenesis Xiaoyi Jin, Naoki Asano, Akira Imatani, Jun Fushiya, Yutaka Kondo, Katsunori Iijima, Tomoyuki Koike, Tooru Shimosegawa Background & Aim: Helicobacter pylori (H.pylori) infection in the stomach causes precancerous gastric mucosal atrophy. We previously reported that Sox2, which is essential for maintainace of the gastric epithelium, is down-regulated in H.pylori infection. On the other hand, Notch1 promotes differentiation and maintainance of stem cells, and overexpression of Notch intracellular domain (NICD) is known to induce cancers in various organs. However, recent studies have shown that loss-of-function of Notch signaling promotes human squamous cell carcinoma. Hence, we aimed to investigate whether Notch1 signaling is affected upon H. pylori infection and to evaluate the role of Notch1 in human gastric carcinogenesis. Methods & Results: We assessed Notch1 expression in human gastric mucosa by immunohistochemistry (IHC). In H. pylori uninfected gastric mucosa, membranous expression of full-length Notch1 was detected in chief cells and parietal cells, where nuclear Sox2 expression was also detected. These expressions of Notch1 and Sox2 were decreased according to the progression of mucosal atrophy in H. pylori infected gastric mucosa. To confirm this result in vivo, we infected C57BL/6J mice with H. pylori for 12 months, and evaluated the expression levels of Notch1 and Sox2 in their stomachs by quantitative real-time PCR (Q-PCR) in addition to histopathological analysis. The stomachs obtained from the infected mice exhibited mucosal atrophic change and significantly decreased expression of Notch1 and Sox2. We then infected the cultures of two gastric epithelial cell lines AGS and GSM06 with H. pylori and assessed the expression of Notch1 and Sox2 by Q-PCR and western blot. The infected gastric epithelial cells showed reduced Notch1 and Sox2 expression compared to uninfected cells. To investigate the interaction between Notch1 and Sox2, we transfected the siRNA for either of them and evaluated the expression of the other. Although suppression of Sox2 did not influence Notch1 expression, knocking down Notch1 led to decreased expression of Sox2. Furthermore, promoter analysis of Sox2 revealed two RBPJ-κ binding sites (-1137/-925), and chromatin immunoprecipication assay showed binding of NICD to these sites. These results suggested that Notch1 directly regulates Sox2. In addition, MTS assay and FACS analysis with Notch1-siRNA transfected gastric epithelial cells exhibited increased proliferation and decreased apoptosis, which may contribute to carcinogenesis. Consistent with the results obtained from above studies, IHC revealed that full-length Notch1 expression was not observed in any cases (n=30) of human gastric cancer . Conclusion: Our study demonstrated that H. pylori infection triggered Notch1 suppression causes gastric mucosal atrophy through the down-regulation of Sox2, and this suggests that loss of Notch1 function contributes to gastric carcinogenesis.
Su1932 H. pylori Might Induce TGF-β1-Induced EMT by Way of cagE Nayoung Kim, Hyun Chang, Seon Mee Park, Yoon Jin Choi, Dong-ho Lee Background/Aims: An epithelial-mesenchymal transition (EMT) allows a polarized epithelial cell to undergo changes that lead to have a mesenchymal cell phenotype, which includes enhanced migratory capacity and invasiveness. Transforming growth factor (TGF-β1) is regarded as the most important factor involved in EMT. Helicobacter pylori (H. pylori) infection is a major risk factor in the development of gastric adenocarcinoma. A study was undertaken to evaluate the induction of EMT by TGF-β1 and to explore the influence of different strains of H. pylori (43504, G69a, HP99, G27cagE+ or G27cagE-) on the expression level of TGF-β1 and EMT markers in gastric epithelial cell line. Materials and Methods: RTqPCR and Western blot were employed to investigate the expression level of TGF-β1 and five EMT markers (Twist, Vimentin, Snail, Slug and E-cadherin). Human gastric epithelial cells (AGS) treated with different concentration recombinant human TGF-β1 (0.1, 1, 10 ng/ml). Also AGS cells were infected with different five H. pylori strains at multiplicity of infection (MOI) 100. Results: Compared to the control, expression levels of EMT markers increased after stimulation with different concentrations of TGF-β1 (P<0.05). The mRNA expression level of TGF-β1 and five EMT markers were significantly increased in wild type G27 and 435O4 strains (P<0.05). Protein expression level of EMT markers increased in H. pylori infected group as well by Western blot. However, G27ΔE induced significantly lower expression of TGF-β1 and five EMT markers in AGS cells than wild type of G27 (P<0.05). Conclusions: These results suggest that H. pylori might induce TGF-β1-induced EMT by way of cag PAI virulence factor cagE.
AGA Abstracts
Su1935 EGFR Signaling Is a Critical Component of Macrophage Responses to Helicobacter pylori Infection Dana M. Hardbower, Daniel P. Barry, M. Blanca Piazuelo, Rupesh Chaturvedi, Keith T. Wilson Background: Macrophage (MΦ) infiltration of the stomach contributes to chronic gastritis in Helicobacter pylori (Hp) infection that results in DNA damage and gastric atrophy, precursors for carcinogenesis. Classical signaling pathways, like NF-κB, control MΦ function, but reports indicate that epidermal growth factor receptor (EGFR) signaling may occur in MΦ. Our aim was to investigate effects of Hp infection on EGFR transactivation in MΦ, and its effects on MΦ polarization and function in vitro and in vivo. Methods: Murine wildtype bone marrow-derived MΦ (BMMacs) and the murine MΦ cell line RAW 264.7 were utilized
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suppresses the development of MGC. To clarify the molecular changes due to H. pylori eradication, in this study, we evaluated differences in molecular alterations related to carcinogenesis in background mucosa of GC between H. pylori positive and negative patients. Materials and Methods: Seventy-seven consecutive patients who underwent ER for GC were enrolled. H. pylori status was analyzed in each patient by two methods: Giemsa staining and serum H. pylori-IgG antibody. Biopsy specimens were obtained from all cases, and DNA was extracted from intestinal metaplasia (IM), a precancerous lesion, via laser capture microdissection. Microsatellite instability (MSI) was evaluated at five loci based on the Bethesda panel; promoter methylation at hMLH1, E-cadherin, p16, and APC was assessed using methylation-specific polymerase chain reaction. Reactivity of monoclonal antibody for colonic phenotype (mAb Das-1) to IM was also evaluated by an immunoperoxidase assay. Results: H. pylori status was negative in 32 of 77 participants (41.6%). The incidence of MSI and hypermethylation at hMLH1, E-cadherin, p16, and APC genes in IM for H. pylori positive and negative patients, respectively, were 47.6%, 23.7%, 10.5% and 56.1% and 36.7%, 6.7%, 3.4%, 38.7% and 35.5%. There were no significant differences in molecular alterations between H. pylori positive and negative cases. mAb Das-1 reactivity to IM was 70.5% in H. pylori positive and 71.0% in H. pylori negative patients, demonstrating no significant difference. Conclusions: Early GC occurs frequently even in H. pylori negative patients. There were no significant differences in molecular alterations in IM between H. pylori positive and negative patients, suggesting that H. pylori eradication may not change the course of molecular alterations in background mucosa once GC has occured in the stomach.
Su1933 Investigating the Role of Helicobacter pylori Pria Protein Aparna Singh, Dusan Blaskovic, Jungsoo Joo, Ming Yan, William G. Coleman Background: In bacteria, PriA protein, a conserved DEXH-type DNA helicase, plays a central role in replication restart at stalled replication forks. Its unique DNA binding property allows it to recognize and stabilize stalled forks and the structures derived from them. PriA plays a very critical role in replication fork stabilization and DNA repair in E. coli and N. gonorrhoeae. In our in vivo expression technology screen, priA gene was induced in vivo when Helicobacter pylori (H. pylori) infects mouse stomach. We decided to elucidate its role in H. pylori infections. Methods: priA gene null mutation was generated by insertion mutagenesis. Kanamycin gene along with its own promoter was inserted at nucleotide 435 of priA gene. The resulting plasmid, ppriA::Kan, was used to transform H. pylori strain SS1 strain by electroporation and natural transformation. Kanamycin-resistant transformants for priA disruption in H. pylori SS1 were verified by PCR analysis. The strain was named as priAKO. We also generated a priA gene complemented strain which contains pHel2 shuttle plasmid construct containing priA gene along with its own promoter. This strain was named as priAKOComp. We did a comparative analysis of WT HpSS1, priA null mutant (priA KO) and priA gene complemented (priAKOComp) strains by inducing mice infections with all three strains. Mice stomachs were harvested at 4 weeks and 8 weeks of infection to determine the colonization levels. Further experiments were also done with these three strains to monitor the growth rate, analyze sensitivity to acid stress, analyze the DNA repair capability and determine the sensitivity to oxidative damage. Results: We observed that the WT HpSS1 strain could colonize mice very well, priAKO strain was unable to colonize mice and the priAKO Comp strain was able to restore the colonization ability. However, the colonization ability of priAKO Comp strain was lower than wild type HpSS1. in-vitro experiments have demonstrated that priAKO strain grows slowly for the first eight hours and after that the growth rate is comparable to wild type strain. priAKO strain has less survival in acidic medium and is also more sensitive to DNA damaging agents as compared to the wild type strain. Conclusion: These data suggest that PriA protein is needed for survival during mice stomach colonization. Ongoing experiments in our laboratory will provide more insight in determining the role of PriA protein in survival and colonization of H. pylori.
Su1931 Genetic and Serological Predictors of H. pylori Infection in Patients With Inflammatory Bowel Disease Brian L. Huang, Jaimin Amin, Michael J. Stewart, Xiaofei Yan, Jessica L. Yoon, Gil Y. Melmed, Andrew Ippoliti, Eric A. Vasiliauskas, Puja Khanna, Marla Dubinsky, Phillip Fleshner, Yodit Alemayehu, Stephan Targan, Dermot P. McGovern, David Q. Shih Background: H. pylori (HP) cause several gastric mucosal diseases including chronic gastritis, PUD, MALT lymphoma, and gastric cancer. Previous studies showed a genetic association between HP infection and an IBD risk SNP ATG16L1 T300A. Other genetic and serological variations on HP infection in IBD is not known. Aim: Identify genetic and serological factors associated with susceptibility to HP infection among IBD patients. Methods: This case control study compared characteristics between non-Hispanic Caucasian IBD patients with documented HP infection (HP+, n=42) by serology, stool antigen test, urease test, or IHC staining to those without HP infection (HP-, n=556). Genetic and serological information were available in all 556 HP- controls and 30 HP+ (after quality control) cases. Logistic regression tests for association with HP infection were performed using the immunochip after correction for population structure with PCA. ≥100,000 Permutations were performed on significant results. Nominal level for genome-wide association was defined as a permuted p>5E05 and association at known IBD SNPs was considered significant with a permuted p>0.05. Association between IBD serology (ASCA, OmpC, I2, p-ANCA, and CBir-1) and HP infection were performed. Results: HP infection was present in 42 of 598 (7%) IBD patients (HP prevalence in non-Hispanic Caucasian in US is approximately 26%). Five loci encoding a total of 6 genes were associated with HP infection in IBD patients at a level consistent with nominal association at the genome-wide level (p<0.00005) including: rs6046489 (Ras interaction-interference proteins, RIN2), rs17188857 (zinc finger protein ZNF521, chromosome translocation protein SS18), rs140226558 (ribosomal protein ANL3), rs72781747 (Protein kinase C theta type, PRKCQ), rs16829789 (GTPase-activating protein, CDGAP). Additionally, 4 previously identified IBD-associated SNP in the IL27 (rs26528), SMAD7 (rs7240004), TRIB1 (rs921720), and the NOD2 frameshift (rs574329 - NOD2fsinsC) were also associated with HP infection in IBD with p<0.05. The previously identified IBD associated ATG16L1 T300A SNP was not associated with HP infection in our IBD patients. Of the IBD serologies, HP infection in IBD is associated with elevated levels of I2 (mean increase of 12 EU, p=0.03). Discussion: Additional 5 genetic loci with nominal association at the genome wide level and 3 known IBD associated loci that are associated with HP infection in IBD patients were identified. These genetic loci are grouped in genes involved in immune regulation (ZNF521, PRKCQ, IL12, SMAD7, NOD2) and oncogenic process (ANL3, RIN2, CDGAP, SS18, SMAD7). The level of I2 serology is elevated in IBD patients with HP infection. Our data suggest that altered bacteria sensing may lead to immune and oncogenic pathways involved in HP associated gastric disease.
Su1934 Loss of Notch1 Function in Helicobacter pylori Contributes to Gastric Mucosal Atrophy and Carcinogenesis Xiaoyi Jin, Naoki Asano, Akira Imatani, Jun Fushiya, Yutaka Kondo, Katsunori Iijima, Tomoyuki Koike, Tooru Shimosegawa Background & Aim: Helicobacter pylori (H.pylori) infection in the stomach causes precancerous gastric mucosal atrophy. We previously reported that Sox2, which is essential for maintainace of the gastric epithelium, is down-regulated in H.pylori infection. On the other hand, Notch1 promotes differentiation and maintainance of stem cells, and overexpression of Notch intracellular domain (NICD) is known to induce cancers in various organs. However, recent studies have shown that loss-of-function of Notch signaling promotes human squamous cell carcinoma. Hence, we aimed to investigate whether Notch1 signaling is affected upon H. pylori infection and to evaluate the role of Notch1 in human gastric carcinogenesis. Methods & Results: We assessed Notch1 expression in human gastric mucosa by immunohistochemistry (IHC). In H. pylori uninfected gastric mucosa, membranous expression of full-length Notch1 was detected in chief cells and parietal cells, where nuclear Sox2 expression was also detected. These expressions of Notch1 and Sox2 were decreased according to the progression of mucosal atrophy in H. pylori infected gastric mucosa. To confirm this result in vivo, we infected C57BL/6J mice with H. pylori for 12 months, and evaluated the expression levels of Notch1 and Sox2 in their stomachs by quantitative real-time PCR (Q-PCR) in addition to histopathological analysis. The stomachs obtained from the infected mice exhibited mucosal atrophic change and significantly decreased expression of Notch1 and Sox2. We then infected the cultures of two gastric epithelial cell lines AGS and GSM06 with H. pylori and assessed the expression of Notch1 and Sox2 by Q-PCR and western blot. The infected gastric epithelial cells showed reduced Notch1 and Sox2 expression compared to uninfected cells. To investigate the interaction between Notch1 and Sox2, we transfected the siRNA for either of them and evaluated the expression of the other. Although suppression of Sox2 did not influence Notch1 expression, knocking down Notch1 led to decreased expression of Sox2. Furthermore, promoter analysis of Sox2 revealed two RBPJ-κ binding sites (-1137/-925), and chromatin immunoprecipication assay showed binding of NICD to these sites. These results suggested that Notch1 directly regulates Sox2. In addition, MTS assay and FACS analysis with Notch1-siRNA transfected gastric epithelial cells exhibited increased proliferation and decreased apoptosis, which may contribute to carcinogenesis. Consistent with the results obtained from above studies, IHC revealed that full-length Notch1 expression was not observed in any cases (n=30) of human gastric cancer . Conclusion: Our study demonstrated that H. pylori infection triggered Notch1 suppression causes gastric mucosal atrophy through the down-regulation of Sox2, and this suggests that loss of Notch1 function contributes to gastric carcinogenesis.
Su1932 H. pylori Might Induce TGF-β1-Induced EMT by Way of cagE Nayoung Kim, Hyun Chang, Seon Mee Park, Yoon Jin Choi, Dong-ho Lee Background/Aims: An epithelial-mesenchymal transition (EMT) allows a polarized epithelial cell to undergo changes that lead to have a mesenchymal cell phenotype, which includes enhanced migratory capacity and invasiveness. Transforming growth factor (TGF-β1) is regarded as the most important factor involved in EMT. Helicobacter pylori (H. pylori) infection is a major risk factor in the development of gastric adenocarcinoma. A study was undertaken to evaluate the induction of EMT by TGF-β1 and to explore the influence of different strains of H. pylori (43504, G69a, HP99, G27cagE+ or G27cagE-) on the expression level of TGF-β1 and EMT markers in gastric epithelial cell line. Materials and Methods: RTqPCR and Western blot were employed to investigate the expression level of TGF-β1 and five EMT markers (Twist, Vimentin, Snail, Slug and E-cadherin). Human gastric epithelial cells (AGS) treated with different concentration recombinant human TGF-β1 (0.1, 1, 10 ng/ml). Also AGS cells were infected with different five H. pylori strains at multiplicity of infection (MOI) 100. Results: Compared to the control, expression levels of EMT markers increased after stimulation with different concentrations of TGF-β1 (P<0.05). The mRNA expression level of TGF-β1 and five EMT markers were significantly increased in wild type G27 and 435O4 strains (P<0.05). Protein expression level of EMT markers increased in H. pylori infected group as well by Western blot. However, G27ΔE induced significantly lower expression of TGF-β1 and five EMT markers in AGS cells than wild type of G27 (P<0.05). Conclusions: These results suggest that H. pylori might induce TGF-β1-induced EMT by way of cag PAI virulence factor cagE.
AGA Abstracts
Su1935 EGFR Signaling Is a Critical Component of Macrophage Responses to Helicobacter pylori Infection Dana M. Hardbower, Daniel P. Barry, M. Blanca Piazuelo, Rupesh Chaturvedi, Keith T. Wilson Background: Macrophage (MΦ) infiltration of the stomach contributes to chronic gastritis in Helicobacter pylori (Hp) infection that results in DNA damage and gastric atrophy, precursors for carcinogenesis. Classical signaling pathways, like NF-κB, control MΦ function, but reports indicate that epidermal growth factor receptor (EGFR) signaling may occur in MΦ. Our aim was to investigate effects of Hp infection on EGFR transactivation in MΦ, and its effects on MΦ polarization and function in vitro and in vivo. Methods: Murine wildtype bone marrow-derived MΦ (BMMacs) and the murine MΦ cell line RAW 264.7 were utilized
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