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The gastric pathogen Helicobacter pylori is known to activate epithelial cell signaling pathways that regulate numerous inflammatory response genes. The aim of this study was to elucidate the pathway leading to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in H. pylori- infected AGS gastric epithelial cells. We find thatH. pylori, via activation of the epidermal growth factor (EGF) receptor activates the small GTP-binding protein Ras, which in turn, mediates ERK1/2 phosphorylation. cag+ strains ofH. pylori are able to induce greater EGF receptor activation than cag− strains, and studies with isogenic mutants indicate that an intact type IV bacterial secretion system is required for this effect. Blockade of EGF receptor activation using tyrphostin AG1478 prevents H. pylori-mediated Ras activation, inhibits ERK1/2 phosphorylation, and substantially decreases interleukin-8 gene expression and protein production. Investigations into the mechanism of EGF receptor activation, using heparin, a metalloproteinase inhibitor and neutralizing antibodies reveal that H. pylori transactivates the EGF receptor via activation of the endogenous ligand heparin-binding EGF-like growth factor. Transactivation of gastric epithelial cell EGF receptors may be instrumental in regulating both proliferative and inflammatory responses induced by cag+ H. pylori infection. The gastric pathogen Helicobacter pylori is known to activate epithelial cell signaling pathways that regulate numerous inflammatory response genes. The aim of this study was to elucidate the pathway leading to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in H. pylori- infected AGS gastric epithelial cells. We find thatH. pylori, via activation of the epidermal growth factor (EGF) receptor activates the small GTP-binding protein Ras, which in turn, mediates ERK1/2 phosphorylation. cag+ strains ofH. pylori are able to induce greater EGF receptor activation than cag− strains, and studies with isogenic mutants indicate that an intact type IV bacterial secretion system is required for this effect. Blockade of EGF receptor activation using tyrphostin AG1478 prevents H. pylori-mediated Ras activation, inhibits ERK1/2 phosphorylation, and substantially decreases interleukin-8 gene expression and protein production. Investigations into the mechanism of EGF receptor activation, using heparin, a metalloproteinase inhibitor and neutralizing antibodies reveal that H. pylori transactivates the EGF receptor via activation of the endogenous ligand heparin-binding EGF-like growth factor. Transactivation of gastric epithelial cell EGF receptors may be instrumental in regulating both proliferative and inflammatory responses induced by cag+ H. pylori infection. interleukin c-Jun N-terminal kinase extracellular signal-regulated kinase mitogenactivated protein kinase heparin binding epidermal growth factor-like growth factor Helicobacter pylori is a pathogenic Gram-negative bacterium that colonizes human gastric mucosa. H. pylori infection has been connected etiologically to peptic ulcer disease (1Kuipers E.J. Thijs J.C. Festen H.P. Aliment. Pharmacol. Ther. 1995; 9 Suppl. 2: 59-69PubMed Google Scholar), mucosa-associated lymphoid tissue lymphoma of the stomach (2Wotherspoon A.C. Ortiz-Hidalgo C. Falzon M.R. Isaacson P.G. Lancet. 1991; 338: 1175-1176Abstract PubMed Scopus (1736) Google Scholar), and gastric adenocarcinoma (3Huang J.Q. Sridhar S. Chen Y. Hunt R.H. Gastroenterology. 1998; 114: 1169-1179Abstract Full Text Full Text PDF PubMed Scopus (826) Google Scholar). H. pylori colonization invariably causes chronic active gastritis, a disease state characterized by neutrophil infiltration of the gastric mucosa and epithelial layer. Interaction of the bacterium with gastric epithelial cells leads to the production of chemokines, such as interleukin-8 (IL-8),1 which in turn causes activation and recruitment of neutrophils to the site of infection. It is now known that attachment of H. pylori to gastric epithelial cells activates multiple signaling pathways that culminate in IL-8 gene transcription. Previous studies have shown that H. pylori is able to induce activation of the transcription factors NF-κB and AP-1, key regulators of many inflammatory genes including IL-8 (4Keates S. Hitti Y.S. Upton M. Kelly C.P. Gastroenterology. 1997; 113: 1099-1109Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 5Glocker E. Lange C. Covacci A. Bereswill S. Kist M. Pahl H.L. Infect. Immun. 1998; 66: 2346-2348Crossref PubMed Google Scholar, 6Meyer-ter-Vehn T. Covacci A. Kist M. Pahl H.L. J. Biol. Chem. 2000; 275: 16064-16072Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 7Naumann M. Wessler S. Bartsch C. Wieland B. Covacci A. Haas R. Meyer T.F. J. Biol. Chem. 1999; 274: 31655-31662Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Moreover, we and others, have recently reported that infection of gastric epithelial cell lines with H. pylori results in the rapid activation of p38, JNK, and ERK1/2 mitogen-activated protein (MAP) kinases (6Meyer-ter-Vehn T. Covacci A. Kist M. Pahl H.L. J. Biol. Chem. 2000; 275: 16064-16072Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 7Naumann M. Wessler S. Bartsch C. Wieland B. Covacci A. Haas R. Meyer T.F. J. Biol. Chem. 1999; 274: 31655-31662Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). However, the mechanisms whereby H. pylori are able to activate gastric epithelial cell MAP kinases are still unclear. The ERK1/2 pathway has been linked to cellular proliferation and differentiation (9Schlessinger J. Cell. 2000; 103: 211-225Abstract Full Text Full Text PDF PubMed Scopus (3537) Google Scholar), however, our previous findings suggest these proteins also participate in proinflammatory cellular responses in gastric epithelial cells. By blocking upstream ERK1/2 phosphorylation using the MEK inhibitor PD98059 we were able to reduce the amount of IL-8 produced by AGS cells in response to H. pylori infection. Interestingly, this effect was not mediated via blockade of NF-κB activation (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). However, it has been demonstrated that H. pylori- mediated AP-1 activation is prevented by PD98059 (6Meyer-ter-Vehn T. Covacci A. Kist M. Pahl H.L. J. Biol. Chem. 2000; 275: 16064-16072Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). The activity of ERK1/2 are generally regulated through the activation of cell surface receptors. One possible mechanism whereby H. pylori may modulate the ERK1/2 pathway is through the EGF receptor. The EGF receptor is a transmembrane receptor with intrinsic tyrosine kinase activity, known to regulate the ERK1/2 pathway, via activation of the small GTP-binding protein Ras. Numerous stimuli are known to cause transactivation of the EGF receptor, including Substance P (10Castagliuolo I. Valenick L. Liu J. Pothoulakis C. J. Biol. Chem. 2000; 275: 26545-26550Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar), bradykinin (11Adomeit A. Graness A. Gross S. Seedorf K. Wetzker R. Liebmann C. Mol. Cell. 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Here, we report that H. pylori is capable of inducing EGF receptor phosphorylation, which is, in part, responsible for ERK1/2 activation in H. pylori- infected AGS cells. In this study, we also examine the downstream effects of EGF receptor activation on IL-8 regulation byH. pylori, and explore the mechanism by which this bacterium induces EGF receptor phosphorylation. AGS gastric epithelial cells (American Type Culture Collection, Rockville, MD) were grown in F-12 HAM medium (pH 7.4: Sigma-Aldrich) supplemented with 10% fetal bovine serum, 100 units/ml penicillin G sodium, and 100 μg/ml streptomycin sulfate. All cultures were maintained at 37 °C in a humidified atmosphere of 95% air and 5% CO2. Cell culture experiments were carried out using 100-mm dishes and 12- or 24-well polypropylene tissue culture plates (Corning Costar, Cambridge, MA). All experiments were carried out using confluent monolayers unless otherwise stated. In some experiments, cells were treated with AG1478 (Calbiochem, La Jolla, CA), batimastat (British Biotech, Oxford, UK), HB-EGF neutralizing antibody, EGF (both from R PubMed Scopus Google Scholar). strains strain were from the culture of the and Helicobacter and have been (17Tummuru M.K. Sharma S.A. M.J. Mol. 1995; PubMed Scopus Google Scholar, Jr., R.M. Miller J.C. M.J. 1995; Google Scholar). H. pylori- were by bacteria in antibiotic-free medium for at 37 at 4,000 for 10 min, and then the medium through a AGS gastric epithelial cells plated onto 100-mm dishes were for to were then incubated with H. pylori bacteria for the were with phosphate-buffered saline and on using of 100 100 and a inhibitor were then and to was by and the EGF receptor were performed using of which was incubated for at °C with of a receptor by an at °C with a of G The were with and proteins were by for in proteins were using and to were then for with 5% in saline with and incubated with the tyrosine were using at a were and with a receptor to protein AGS cells were grown on plates and maintained in medium for to the H. pylori were in and for of the of the the monolayers were 3 with phosphate-buffered saline and with 10% were then to 100 °C for min, and of onto a 10% After the proteins were onto and for at with a 5% of in with was by an at °C with the MAP kinase antibodies in blocking The were then 3 with and incubated at for with was for MAP kinase was to and MAP kinase are by phosphorylation at and MAP kinase was to by phosphorylation at and MAP kinase was to and MAP kinase are by phosphorylation at and All antibodies were from Cell to of the of the IL-8 gene was into the expression and The was by using for the expression and The IL-8 gene and a gene were into AGS gastric epithelial cells using to the AGS with were by to the culture and with the IL-8 were by their to to R 113: 1099-1109Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, Pothoulakis C. Keates S. Warny M. Keates A.C. Kelly C.P. J. 1997; Google Scholar, Jr., Keates S. Kelly C.P. Infect. Immun. 1998; 66: PubMed Google Scholar). were performed using for Unless stated by were for Ras activation was using a of protein from treated with of for at was incubated for at °C with of The were 3 with and resuspended in of for min, and then onto a were to and the was for with 5% in phosphate-buffered The was incubated at °C with an at a Ras was then using an and a a the Ras the human was from by with and The was then into the with and cells were at cells 100-mm and incubated with 10 of 10% fetal bovine medium for The medium was with medium to The and were in a of and to using to the the were through and the were or at was in an and were by C. MA). the EGF receptor is by H. pylori from AGS cells infected with H. pylori for were with a receptor of the using the demonstrated the of a protein of of the cells with the EGF receptor inhibitor tyrphostin AG1478 for was able to H. pylori- mediated EGF receptor phosphorylation. that the protein was the EGF receptor the was with an receptor that H. pylori is able to induce phosphorylation of the EGF receptor in AGS cells of infection. experiments an in tyrosine phosphorylation of the EGF receptor as as infection not of the EGF receptor is known to activate the pathway in the phosphorylation of the ERK1/2 activation we in H. pylori- infected AGS cells (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar) was mediated through activation of the EGF we tyrphostin an that prevents EGF receptor kinase shown in H. pylori was able to induce phosphorylation of ERK1/2 by and this effect was the cells were with AG1478 H. pylori- mediated ERK1/2 phosphorylation was prevented at by AG1478 and by at the as by pathways is we this inhibitor also the phosphorylation of or in H. pylori infected AGS cells. However, in to our findings for AG1478 effect on or phosphorylation and indicate that H. pylori induced activation of ERK1/2 is, at in part, to phosphorylation of the EGF receptor, EGF receptor activation not pylori- induced or phosphorylation. we demonstrated that activation the ERK1/2 pathway by H. pylori is of the mechanisms whereby the bacterium is able to regulate production (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). We that blockade of the EGF receptor as an upstream of the ERK1/2 pathway may have effects on IL-8 gene this we AGS cells with an IL-8 shown in of these cells with H. pylori for a in IL-8 However, activity was to EGF receptor phosphorylation was prevented by with AG1478 with our transcription was a of IL-8 protein production by AGS cells in response to infection with H. pylori for a which was the cells were with the EGF receptor inhibitor AG1478 We have that both cag+ and cag− strains ofH. pylori were capable of the ERK1/2 pathway, in the of activation (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). The ERK1/2 phosphorylation in AGS cells infected with cag− H. pylori was with infected with cag+ we activation of the EGF receptor was also on the cag of the the of EGF receptor tyrosine phosphorylation cells were infected with strain or cag− strain ofH. pylori a We find that strain induces a activation of the EGF receptor, as with the activation to with the of the cag+ and cag− H. pylori to induce phosphorylation of also shown in a and cag− H. pylori in their to induce activation of the EGF receptor, we isogenic mutants of H. pylori induce the response as a wild type cag+ strain demonstrated in phosphorylation of the EGF receptor by the was than for the isogenic wild type H. pylori In induced a activation of the EGF receptor with the wild type suggest that activation of the EGF receptor by H. pylori an intact type IV not the of the protein into the it has been reported that culture from H. pylori was able to cause of the EGF receptor R. R.M. M.J. J. 1998; Google Scholar), we also the effect of a ofH. pylori on gastric epithelial cell EGF receptor phosphorylation. shown in the of the vacA gene effect on the of the bacteria to induce EGF receptor phosphorylation, as with the wild type of the EGF receptor, as as cell surface the of for on the small G protein Ras. in the active Ras with proteins such as and which in turn leads to the phosphorylation of the mechanism leading to ERK1/2 phosphorylation, we Ras H. pylori infection of AGS and we this activation using results a activation of Ras, at min, which is by of the cells with AG1478 EGF as was to Ras activation 10 EGF activation of Ras was also prevented by with cell from these experiments were also for and ERK1/2 to examine the Ras activation and ERK1/2 phosphorylation and to of protein for the Ras and Interestingly, ERK1/2 phosphorylation was prevented with H. pylori AG1478 were still that may be than mechanism in H. pylori activation of the ERK1/2 We Ras activation byH. pylori was upstream of ERK1/2 phosphorylation. this we Ras in AGS cells using and ERK1/2 phosphorylation in response pylori infection. shown in ERK1/2 phosphorylation is in cells. However, H. pylori and EGF a of ERK1/2 phosphorylation in the cells. EGF activation of ERK1/2 was in cells Ras, H. pylori- mediated ERK1/2 activation was findings that ERK1/2 activation by H. pylori be mediated via both and examine factors byH. pylori were responsible for phosphorylation of the EGF receptor, we incubated AGS cells with both bacteria or medium for H. pylori- medium was to induce EGF receptor phosphorylation that the bacterium and the cell is for of EGF receptor phosphorylation. with our previous thatH. pylori- medium is to induce ERK1/2 phosphorylation (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). Previous studies have shown in a of the EGF receptor the mechanism of E. H. M. R. Wallasch C. Ullrich A. Nature. 1999; PubMed Scopus Google Scholar). HB-EGF then the EGF receptor leading to phosphorylation. HB-EGF as of the EGF receptor and the of heparin has been shown to with for HB-EGF binding M. 1997; Google Scholar). We infected AGS cells with H. pylori in the of heparin shown in heparin H. pylori-mediated EGF receptor phosphorylation. The from the heparin experiments to examine an endogenous ligand of the EGF receptor, was EGF receptor activation in H. pylori- infected AGS cells. In of this we that a HB-EGF neutralizing H. pylori- mediated activation of the EGF receptor The HB-EGF neutralizing was also to cause a by in H. pylori- ERK1/2 phosphorylation of HB-EGF and EGF receptor has been reported to be on the of We the that H. pylori may be these and cause the of the of We this by the cells with batimastat a metalloproteinase shown in we that batimastat EGF receptor phosphorylation by H. In we that this inhibitor also reduce ERK1/2 phosphorylation induced by H. pylori We and have reported that H. pylori activates a of MAP kinases in gastric epithelial cell lines (6Meyer-ter-Vehn T. Covacci A. Kist M. Pahl H.L. J. Biol. Chem. 2000; 275: 16064-16072Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 7Naumann M. Wessler S. Bartsch C. Wieland B. Covacci A. Haas R. Meyer T.F. J. Biol. Chem. 1999; 274: 31655-31662Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar, S. M. W. S. Haas R. B. Meyer T.F. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). of these pathways a key in the expression of the proinflammatory IL-8 (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar). However, the mechanisms whereby H. pylori activates these signaling pathways are still We now report that H. pylori induce phosphorylation of the EGF receptor in AGS gastric epithelial cells. H. pylori- induced EGF receptor phosphorylation leads to activation of Ras, which is able to ERK1/2 phosphorylation, which in turn IL-8 gene expression and protein production. We find that EGF receptor phosphorylation mediated by H. pylori is an intact type IV bacterial Moreover, we find that the mechanism the of EGF receptor phosphorylation by H. pylori activation of the EGF receptor ligand One of our study is that is a activation of the EGF receptor the H. pylori strain a of genes known as The cag for that on to a type IV bacterial secretion system S. Lange C. J.E. M. R. Covacci A. S. A. 1996; PubMed Scopus Google Scholar). It has been reported that the of the or of cag genes in an to activate AP-1, and MAP kinase pathways (6Meyer-ter-Vehn T. Covacci A. Kist M. Pahl H.L. J. Biol. Chem. 2000; 275: 16064-16072Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 7Naumann M. Wessler S. Bartsch C. Wieland B. Covacci A. Haas R. Meyer T.F. J. Biol. 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We have demonstrated through the of an isogenic that this protein not to a in inducing EGF receptor phosphorylation. is with our of in that the protein not induce an inflammatory and in MAP kinase activation (8Keates S. Keates A.C. Warny M. Peek Jr., R.M. Murray P.G. Kelly C.P. J. Immunol. 1999; 163: 5552-5559PubMed Google Scholar), NF-κB activation S.A. M.K. M.J. J. Immunol. 1998; Google Scholar), or IL-8 production S. Lange C. J.E. M. R. Covacci A. S. A. 1996; PubMed Scopus Google Scholar). our study we also that the vacuolating toxin produced byH. pylori in H. pylori- induced EGF receptor phosphorylation, we our wild type and mutants in their to induce EGF receptor phosphorylation. It has been reported that H. pylori vacuolating toxin cause of the EGF receptor, and ERK1/2 activation in cells R. R.M. M.J. J. 1998; Google Scholar). In to we find that intact H. pylori were to induce phosphorylation of the EGF receptor and activate the ERK1/2 signaling We however, examine the effects of vacuolating toxin in our system or the effects of H. pylori on cells. we on the signaling that ofH. pylori with gastric epithelial cells. We have demonstrated for the through of EGF receptor phosphorylation H. pylori is capable of the small GTP-binding protein Ras, which activates a signaling in ERK1/2 phosphorylation. However, in our experiments using an EGF receptor inhibitor and Ras we were to blockade of ERK1/2 phosphorylation induced by H. that pathways through which the bacteria are able to induce ERK1/2 phosphorylation. is by a study that H. pylori the gene through ERK1/2 activation, via a Ras pathway S. M. W. S. Haas R. B. Meyer T.F. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). We have that H. pylori induced phosphorylation of the EGF receptor is mediated through the of EGF receptor Previous studies have also the EGF receptor and H. M. A. M.J. R. J. 1998; PubMed Scopus Google Scholar) reported that by of H. pylori or with cells for were able to both and HB-EGF We find that rapid activation of the EGF receptor by H. pylori is not mediated through the of bacterial to be of HB-EGF from the cell is a of of and not to be mediated via production of of transmembrane HB-EGF M. 1997; Google Scholar). our system the H. pylori and gastric epithelial cells we out the that factors by the bacteria may a in EGF receptor ligand production the of infection. Transactivation of the EGF receptor by numerous receptors has now been as a in signaling (13Roudabush F.L. Pierce K.L. Maudsley S. Khan K.D. Luttrell L.M. J. Biol. Chem. 2000; 275: 22583-22589Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, E. H. M. R. Wallasch C. Ullrich A. Nature. 1999; PubMed Scopus Google A. 2000; PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, S. H. Y. K. Y. Y. H. Y. Y. A. E. S. T. PubMed Scopus Google Scholar). The mechanism for activation of the EGF receptor these to be through such as are able to the of HB-EGF of which in turn and activates the EGF receptor, and activates the MAP kinase E. H. M. R. Wallasch C. Ullrich A. Nature. 1999; PubMed Scopus Google Scholar). We now report the that H. EGF receptor phosphorylation is mediated through and is prevented by the metalloproteinase inhibitor of the gastric epithelial cell byH. pylori to induce HB-EGF which in turn activates EGF receptor and ERK1/2 We that H. pylori may cause transactivation of the EGF receptor by with a receptor on the surface of the gastric epithelial or through of bacterial proteins into the transactivation of the EGF receptor may be instrumental in inducing the proliferative and inflammatory responses in infection of the gastric H.
Keates et al. (Sat,) studied this question.