Helicobacter pylori and mitogen-activated protein kinases regulate the cell cycle, proliferation and apoptosis in gastric epithelial cells.
OBJECTIVE
Helicobacter pylori infection activates mitogen-activated protein kinases (MAPK) and modulates cell proliferation and apoptosis. However, the relationship between H. pylori infection and MAPK signaling in controlling cell proliferation and apoptosis is not clear, nor has the role of MAPK on the gastric epithelial cell cycle and proliferation been established. Therefore, we investigated the effects of H. pylori infection and MAPK inhibition on these processes.


METHODS
Gastric epithelial cell lines (AGS and MKN45) were infected with H. pylori and/or treated with MAPK inhibitors. Cell cycle and apoptosis were measured by flow cytometry. Cell cycle proteins and proliferation were monitored by western blot and cell count, respectively.


RESULTS
Infection with H. pylori resulted in dose-dependent MAPK activation, cell cycle arrest, reduced proliferation and increased apoptosis. The effect of H. pylori and MAPK at various cell cycle checkpoints was noted: MEK1/2 and p38 inhibition increased H. pylori-induced cell cycle G(1) arrest, while JNK inhibition reduced G(1) arrest. MEK1/2 inhibition increased p21, p27 and cyclin E and JNK inhibition additionally increased cyclin D1 expression. Both inhibitors decreased cell proliferation. All inhibitors enhanced apoptosis after H. pylori infection. We also detected MAPK cross-talk in AGS cells: p38 and JNK inhibitors increased ERK activation. The p38 inhibitor increased JNK and the MEK1/2 inhibitor decreased JNK activation only during H. pylori infection.


CONCLUSIONS
These results suggest H. pylori and MAPK differentially regulate the cell cycle, proliferation and apoptosis in gastric epithelial cells. The imbalance between H. pylori infection and MAPK activation likely contributes to the H. pylori-induced pathogenesis.
Ding
Song-Ze
SZ
Department of Microbiology, The University of Virginia Health System, Charlottesville, Virginia 22908-0734, USA.
Smith
Michael F
MF
Goldberg
Joanna B
JB
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D016481:Helicobacter Infections / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases