NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.
The Helicobacter pylori immunodominant protein, CagA, is associated with severe gastritis and carcinoma. Injection of CagA into gastric epithelial cells by type IV secretion leads to actin-cytoskeletal rearrangements and cell scattering. CagA has been reported to have no role in the induction of transcription factor NF-kappaB and IL-8, which are crucial determinants for chronic inflammation. Here, we provide several lines of evidence showing that CagA is able to induce IL-8 in a time- and strain-dependent manner. We also show that by exchanging specific cagA genes, high IL-8-inducing H. pylori strains could be converted into low inducing strains and vice versa. Our results suggest that IL-8 release induced by CagA occurs via a Ras-->Raf-->Mek-->Erk-->NF-kappaB signaling pathway in a Shp-2- and c-Met-independent manner. Thus, CagA is a multifunctional protein capable of effecting both actin remodeling and potentiation of chemokine release.
Department of Medical Microbiology, Otto von Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
Sabine
S
Brandt
Terry
T
Kwok
Roland
R
Hartig
Wolfgang
W
König
Steffen
S
Backert
D000199:Actins / Q000737:chemistry; D021581:Active Transport, Cell Nucleus; D000942:Antigens, Bacterial / Q000737:chemistry / Q000378:metabolism*; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003599:Cytoskeleton / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000382:microbiology; D005753:Gastric Mucosa / Q000378:metabolism; D005816:Genetic Complementation Test; D044404:Genomic Islands; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000382:microbiology; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D000199:Actins; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C080866:cagA protein, Helicobacter pylori; D049452:Green Fluorescent Proteins; D019859:Proto-Oncogene Proteins c-met; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases