title: Macrophage migration inhibitory factor stimulated by Helicobacter pylori increases proliferation of gastric epithelial cells.
abstract: OBJECTIVE
  Helicobacter pylori (H pylori) is associated with increased gastric inflammatory and epithelial expression of macrophage migration inhibitory factor (MIF) and gastric epithelial cell proliferation. This study aimed at determining whether H pylori directly stimulates release of MIF in monocytes, whether the cag pathogenicity island (PAI) is involved for this function, and whether MIF stimulated by H pylori increases gastric epithelial cell proliferation in vitro.
  
  
  METHODS
  A cytotoxic wild-type H pylori strain (TN2), its three isogenic mutants (TN2Deltacag, TN2DeltacagA and TN2DeltacagE) were co-cultured with cells of a human monocyte cell line, THP-1, for 24 h at different organism/cell ratios. MIF in the supernatants was measured by an ELISA. Cells of a human gastric cancer cell line, MKN45, were then co-cultured with the supernatants, with and without monoclonal anti-MIF antibody for 24 h. The cells were further incubated for 12 h after addition of 3H-thymidine, and the levels of incorporation of 3H-thymidine were measured with a liquid scintillation counter.
  
  
  RESULTS
  The wild-type strain and the isogenic mutants, TN2DeltacagA and TN2 DeltacagE, increased MIF release at organism/cell ratios of 200/1 and 400/1, but not at the ratios of 50/1 and 100/1. However, the mutant TN2delta cag did not increase the release of MIF at any of the four ratios. 3H-thymidine readings for MKN-45 cells were significantly increased with supernatants derived from the wild-type strain and the mutants TN2DeltacagA and TN2DeltacagE, but not from the mutant TN2Deltacag. Moreover, in the presence of monoclonal anti-MIF antibody, the stimulatory effects of the wild-type strain on cell proliferation disappeared.
  
  
  CONCLUSIONS
  H pylori stimulates MIF release in monocytes, likely through its cag PAI, but not related to cagA or cagE. H pylori-stimulated monocyte culture supernatant increases gastric cell proliferation, which is blocked by anti-MIF antibody, suggesting that MIF plays an important role in H pylori-induced gastric epithelial cell proliferation.
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Harry Hua-Xiang
authors.initials: HH
authors.lastname: Xia
authors.forename: Shiu Kum
authors.initials: SK
authors.lastname: Lam
authors.forename: Annie O O
authors.initials: AO
authors.lastname: Chan
authors.forename: Marie Chia Mi
authors.initials: MC
authors.lastname: Lin
authors.forename: Hsiang Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Berg
authors.forename: Benjamin Chun-Yu
authors.initials: BC
authors.lastname: Wong
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000473:pathology*; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000382:microbiology*; D009154:Mutation; D013270:Stomach / Q000382:microbiology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D008263:Macrophage Migration-Inhibitory Factors; C103937:PicB protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori