Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has recently been implicated in carcinogenesis. Helicobacter pylori, which is closely linked to gastric cancer, induces the gastric epithelium to produce proinflammatory cytokines, including MIF. MIF can bind to CD74, which we have previously shown to be highly expressed on the surface of gastric epithelial cells (GEC) during H. pylori infection. In this study, we sought to investigate the role of the H. pylori-induced MIF on epithelial proliferation and procarcinogenic events. Upon establishing a role for the H. pylori CagA virulence factor in MIF production, MIF binding to CD74 on GEC was confirmed. rMIF and H. pylori were shown to increase GEC proliferation, which was decreased when cagA- strains were used and when CD74 was blocked by mAbs. Apoptosis was also decreased by MIF, but increased by cagA- strains that induced much lower amounts of MIF than the wild-type bacteria. Furthermore, MIF binding to CD74 was also shown to decrease p53 phosphorylation and up-regulate Bcl-2 expression. This data describes a novel system in which an H. pylori virulence factor contributes to the production of a host factor that in turn up-regulates procarcinogenic events by the gastric epithelium.
Beswick
Ellen J
EJ
Department of Pediatrics, University of Texas, Galveston, TX 77555, USA.
Pinchuk
Irina V
IV
Suarez
Giovanni
G
Sierra
Johanna C
JC
Reyes
Victor E
VE
D000942:Antigens, Bacterial / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000276:immunology; D005753:Gastric Mucosa / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000276:immunology / Q000472:pathogenicity; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011230:Precancerous Conditions / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D011485:Protein Binding / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology; D037521:Virulence Factors / Q000502:physiology
D000942:Antigens, Bacterial; D000944:Antigens, Differentiation, B-Lymphocyte; D001426:Bacterial Proteins; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; C045084:invariant chain