Abstract
Human intestinal epithelial cells up-regulate the expression of an inflammatory gene program in response to infection with a spectrum of different strains of enteroinvasive bacteria. The conserved nature of this program suggested that diverse signals, which are activated by enteroinvasive bacteria, can be integrated into a common signaling pathway that activates a set of proinflammatory genes in infected host cells. Human intestinal epithelial cell lines, HT-29, Caco-2, and T84, were infected with invasive bacteria that use different strategies to induce their uptake and have different intracellular localizations (i.e., Salmonella dublin, enteroinvasive Escherichia coli, or Yersinia enterocolitica). Infection with each of these bacteria resulted in the activation of TNF receptor associated factors, two recently described serine kinases, I kappa B kinase (IKK) alpha and IKK beta, and increased NF-kappa B DNA binding activity. This was paralleled by partial degradation of I kappa B alpha and I kappa B epsilon in bacteria-infected Caco-2 cells. Mutant proteins that act as superrepressors of IKK beta and I kappa B alpha inhibited the up-regulated transcription and expression of downstream targets genes of NF-kappa B that are key components of the epithelial inflammatory gene program (i.e., IL-8, growth-related oncogene-alpha, monocyte chemoattractant protein-1, TNF-alpha, cyclooxygenase-2, nitric oxide synthase-2, ICAM-1) activated by those enteroinvasive bacteria. These studies position NF-kappa B as a central regulator of the epithelial cell innate immune response to infection with enteroinvasive bacteria.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Caco-2 Cells
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Chemokine CCL2 / antagonists & inhibitors
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Chemokine CXCL1
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Chemokines, CXC*
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Chemotactic Factors / biosynthesis
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Enterobacteriaceae Infections / genetics
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Enterobacteriaceae Infections / immunology*
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Enzyme Activation / immunology
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Gene Expression Regulation / immunology
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Gene Expression Regulation, Bacterial / immunology
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Genes, Reporter / immunology
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Growth Substances / biosynthesis
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HT29 Cells
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Humans
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I-kappa B Kinase
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I-kappa B Proteins*
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Immunity, Innate
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Intercellular Signaling Peptides and Proteins*
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / genetics
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / microbiology
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Isoenzymes / biosynthesis
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Membrane Proteins
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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NF-kappa B / physiology*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase Type II
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / immunology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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CXCL1 protein, human
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Chemokine CCL2
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Chemokine CXCL1
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Chemokines, CXC
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Chemotactic Factors
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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DNA-Binding Proteins
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Growth Substances
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I-kappa B Proteins
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Intercellular Signaling Peptides and Proteins
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Interleukin-8
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Isoenzymes
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Membrane Proteins
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NF-kappa B
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NFKBIA protein, human
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Tumor Necrosis Factor-alpha
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Intercellular Adhesion Molecule-1
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NF-KappaB Inhibitor alpha
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human