Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia.
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-kappaB 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 IkappaBalpha in airway epithelial cells, implicating this cell type as an important locus of NF-kappaB 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 IkappaBalpha and IkappaBbeta 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.
Quinton
Lee J
LJ
Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA 02115, USA.
Jones
Matthew R
MR
Simms
Benjamin T
BT
Kogan
Mariya S
MS
Robson
Bryanne E
BE
Skerrett
Shawn J
SJ
Mizgerd
Joseph P
JP
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000382:microbiology; D051550:I-kappa B Kinase / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011018:Pneumonia, Pneumococcal / Q000276:immunology*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016207:Cytokines; D007375:Interleukin-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase