Functions of IkappaB proteins in inflammatory responses to Escherichia coli LPS in mouse lungs.
Acute inflammation induced by intrapulmonary LPS requires nuclear factor (NF)-kappaB RelA. This study elucidates the effects of intrapulmonary LPS on IkappaB proteins, endogenous inhibitors of RelA, and the effects of deficiency of IkappaB-beta. IkappaB-alpha, IkappaB-beta, and IkappaB-epsilon each complexed with RelA in uninfected murine lungs. Intratracheal instillation of LPS induced the degradation of IkappaB-alpha and IkappaB-beta, as measured by the loss of immunoreactive proteins in non-nuclear fractions. Degradation was apparent by 2 h and sustained through 6 h. In contrast, net IkappaB-epsilon content increased over this period. The small amounts of IkappaB-alpha and IkappaB-beta that were detected in nuclear fractions from the lungs also decreased over this time frame, whereas intranuclear NF-kappaB content (including both RelA and p50) increased. The hypophosphorylated form of IkappaB-beta, which facilitates transcription induced by NF-kappaB, was not detected. Neutrophil recruitment and edema accumulation did not differ between wild type mice and gene-targeted mice deficient in IkappaB-beta, suggesting that IkappaB-beta is not specifically required for these responses. Altogether, these data suggest that RelA is liberated during LPS-induced pulmonary inflammation by the regulated degradation of both IkappaB-alpha and IkappaB-beta. In the absence of IkappaB-beta, IkappaB-alpha or other inhibitory proteins can regulate NF-kappaB functions essential to acute neutrophil emigration in the lungs.
Mizgerd
Joseph P
JP
Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA. jmizgerd@hsph.harvard.edu
Scott
Martin L
ML
Spieker
Matt R
MR
Doerschuk
Claire M
CM
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004487:Edema / Q000378:metabolism / Q000503:physiopathology; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000378:metabolism / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008025:Ligases / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000378:metabolism; D010766:Phosphorylation; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000503:physiopathology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases