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Functions of IB Proteins in Inflammatory Responses to Escherichia coli LPS in Mouse Lungs

Physiology Program, Harvard School of Public Health, Boston; and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Address correspondence to: Joseph P. Mizgerd, S.D., Physiology Program, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: jmizgerd{at}hsph.harvard.edu

Acute inflammation induced by intrapulmonary LPS requires nuclear factor (NF)-B RelA. This study elucidates the effects of intrapulmonary LPS on IB proteins, endogenous inhibitors of RelA, and the effects of deficiency of IB-ß. IB-, IB-ß, and IB- each complexed with RelA in uninfected murine lungs. Intratracheal instillation of LPS induced the degradation of IB- and IB-ß, 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 IB- content increased over this period. The small amounts of IB- and IB-ß that were detected in nuclear fractions from the lungs also decreased over this time frame, whereas intranuclear NF-B content (including both RelA and p50) increased. The hypophosphorylated form of IB-ß, which facilitates transcription induced by NF-B, was not detected. Neutrophil recruitment and edema accumulation did not differ between wild type mice and gene-targeted mice deficient in IB-ß, suggesting that IB-ß 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 IB- and IB-ß. In the absence of IB-ß, IB- or other inhibitory proteins can regulate NF-B functions essential to acute neutrophil emigration in the lungs.

Abbreviations: antibody, Ab • electrophoretic mobility shift assay, EMSA • nuclear factor, NF • red blood cell, RBC • wild type, WT

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