Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia.
While signal transducer and activator of transcription (STAT) 3 signaling has been linked to multiple pathways influencing immune function and cell survival, the direct influence of this transcription factor on innate immunity and tissue homeostasis during pneumonia is unknown. Human patients with dominant-negative mutations in the Stat3 gene develop recurrent pneumonias, suggesting a role for STAT3 in pulmonary host defense. We hypothesized that alveolar epithelial STAT3 is activated by IL-6 family cytokines and is required for effective responses during gram-negative bacterial pneumonia. STAT3 phosphorylation was increased in pneumonic mouse lungs and in murine lung epithelial (MLE)-15 cells stimulated with pneumonic bronchoalveolar lavage fluid (BALF) through 48 hours of Escherichia coli pneumonia. Mice lacking active STAT3 in alveolar epithelial cells (Stat3(Delta/Delta)) had fewer alveolar neutrophils and more viable bacteria than control mice early after intratracheal E. coli. By 48 hours after E. coli infection, however, lung injury was increased in Stat3(Delta/Delta) mice. Bacteria were cleared from lungs of both genotypes, albeit more slowly in Stat3(Delta/Delta) mice. Of the IL-6 family cytokines measured in lungs from infected C57BL/6 mice, IL-6, oncostatin M, leukemia inhibitory factor (LIF), and IL-11 were significantly elevated. Neutralization studies demonstrated that LIF and IL-6 mediated BALF-induced STAT3 activation in MLE-15 cells. Together, these results indicate that during E. coli pneumonia, select IL-6 family members activate alveolar epithelial STAT3, which functions to promote neutrophil recruitment and to limit both infection and lung injury.
Quinton
Lee J
LJ
Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
Jones
Matthew R
MR
Robson
Bryanne E
BE
Simms
Benjamin T
BT
Whitsett
Jeffrey A
JA
Mizgerd
Joseph P
JP
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018410:Pneumonia, Bacterial / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A