Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination.
Epithelia of the vertebrate intestinal tract characteristically maintain an inflammatory hyporesponsiveness toward the lumenal prokaryotic microflora. We report the identification of enteric organisms (nonvirulent Salmonella strains) whose direct interaction with model human epithelia attenuate synthesis of inflammatory effector molecules elicited by diverse proinflammatory stimuli. This immunosuppressive effect involves inhibition of the inhibitor kappaB/nuclear factor kappaB (IkappaB/NF-kappaB) pathway by blockade of IkappaB-alpha degradation, which prevents subsequent nuclear translocation of active NF-kappaB dimer. Although phosphorylation of IkappaB-alpha occurs, subsequent polyubiquitination necessary for regulated IkappaB-alpha degradation is completely abrogated. These data suggest that prokaryotic determinants could be responsible for the unique tolerance of the gastrointestinal mucosa to proinflammatory stimuli.
Neish
A S
AS
Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. aneish@emory.edu
Gewirtz
A T
AT
Zeng
H
H
Young
A N
AN
Hobert
M E
ME
Karmali
V
V
Rao
A S
AS
Madara
J L
JL
D002467:Cell Nucleus / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D020672:I-kappa B Proteins; D018836:Inflammation Mediators / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology*; D007976:Leupeptins / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012475:Salmonella / Q000472:pathogenicity / Q000502:physiology*; D012486:Salmonella typhimurium / Q000472:pathogenicity / Q000502:physiology; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016209:Interleukin-8; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D051176:beta Catenin; D000072000:NF-KappaB Inhibitor alpha; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde