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Functions and Regulation of NF-B RelA during Pneumococcal Pneumonia¹

Lee J. Quinton^*, Matthew R. Jones^*, Benjamin T. Simms^*, Mariya S. Kogan^*, Bryanne E. Robson^*, Shawn J. Skerrett and Joseph P. Mizgerd^2,*

^* Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA 02115; and Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104

Eradication of bacteria in the lower respiratory tract depends on the coordinated expression of proinflammatory cytokines and consequent neutrophilic inflammation. To determine the roles of the NF-B subunit RelA in facilitating these events, we infected RelA-deficient mice (generated on a TNFR1-deficient background) with Streptococcus pneumoniae. RelA deficiency decreased cytokine expression, alveolar neutrophil emigration, and lung bacterial killing. S. pneumoniae killing was also diminished in the lungs of mice expressing a dominant-negative form of IB in airway epithelial cells, implicating this cell type as an important locus of NF-B activation during pneumonia. To study mechanisms of epithelial RelA activation, we stimulated a murine alveolar epithelial cell line (MLE-15) with bronchoalveolar lavage fluid (BALF) harvested from mice infected with S. pneumoniae. Pneumonic BALF, but not S. pneumoniae, induced degradation of IB and IB and rapid nuclear accumulation of RelA. Moreover, BALF-induced RelA activity was completely abolished following combined but not individual neutralization of TNF and IL-1 signaling, suggesting either cytokine is sufficient and necessary for alveolar epithelial RelA activation during pneumonia. Our results demonstrate that RelA is essential for the host defense response to pneumococcus in the lungs and that RelA in airway epithelial cells is primarily activated by TNF and IL-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL68153, HL079392, ES00002, and HL07118. L.J.Q. was supported by an American Lung Association Senior Research Fellowship. M.R.J. was supported by an American Physiological Society Fellowship in Functional Genomics.

² Address correspondence and reprint requests to Dr. Joseph P. Mizgerd, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail address: jmizgerd{at}hsph.harvard.edu

³ Abbreviations used in this paper: dn, dominant negative; AM, alveolar macrophage; BALF, bronchoalveolar lavage fluid; i.t., intratracheal; LIX, LPS-induced CXC chemokine; MLE, murine lung epithelial; rm, recombinant murine; sIL-IR, IL-1 signaling; SP19, type 19 Streptococcus pneumoniae; SP3, type 3 Streptococcus pneumoniae; SPC, surfactant protein-C; WT, wild type.

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