Roles of Interleukin‐6 in Activation of STAT Proteins and Recruitment of Neutrophils during<i>Escherichia coli</i>Pneumonia

Jones, Matthew R.; Quinton, Lee J.; Simms, B. T.; Lupa, Michal M.; Kogan, Mariya S.; Mizgerd, Joseph P.

doi:10.1086/499312

Cited by 92 publications

(107 citation statements)

References 70 publications

(82 reference statements)

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“…IL-6 is also expressed in the lungs and is required for maximal neutrophil recruitment and bacterial killing (25,47). In the present study, expression of these cytokines, neutrophilic inflammation, and bacterial killing were dependent on the NF-B subunit RelA.…”

Section: Discussionsupporting

confidence: 52%

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Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

127

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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-κB 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 IκBα in airway epithelial cells, implicating this cell type as an important locus of NF-κB 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 IκBα and IκBβ 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.

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Section: Discussionsupporting

confidence: 52%

“…Probes contained the reporter dye 6-FAM at the 5Ј end and Black Hole Quencher-1 at the 3Ј end. For each sample, values were normalized to the content of 18S rRNA (25,26) and expressed the fold induction vs TNFR1-deficient/RelA ϩ/ϩ mice.…”

Section: Pneumoniamentioning

confidence: 99%

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Quinton

Jones

Simms

et al. 2007

The Journal of Immunology

127

View full text Add to dashboard Cite

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“…Interestingly, the Rho kinase inhibitor and the JNK inhibitor induced similar reduction in IL-6 secretion, despite the fact that the Rho kinase inhibitor only partially inhibited early JNK activation. Because IL-6 deficiency and JNK inhibition reduce inflammatory responses in the lungs, Rho kinase may regulate inflammatory responses in vivo by regulating the JNK-IL-6 pathway (6,7,17,53).…”

Section: Discussionmentioning

confidence: 99%

Activation of Rho Kinase by TNF-α Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells

Mong

Petrulio

Kaufman

et al. 2008

The Journal of Immunology

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TNF‐α induces complex signaling events in endothelial cells (ECs), resulting in gene transcription and increased junctional permeability. This study examined the activation of the RhoA/Rho kinase pathway induced by TNF‐α in primary human pulmonary microvascular ECs and its role in EC responses to TNF‐α. Activation of RhoA was induced by TNF‐α within five minutes. This increase in RhoA activity rapidly decreased, and a late activation of RhoA was induced three hours after TNF‐α treatment. This late but not early RhoA activation was associated with its accumulation in focal aggregates near EC edges. TNF‐α also induced Rho kinase activation that was observed within five minutes and lasted for at least three hours. Inhibition of Rho kinase prevented TNF‐α‐induced cytoskeletal changes and permeability increases. TNF‐α also induced activation of JNK that peaked at fifteen minutes and lasted for at least three hours, and inhibition of Rho kinase prevented TNF‐α‐induced early and late JNK activation. Inhibition of JNK activation, however, did not prevent TNF‐α‐induced cytoskeletal changes, suggesting that Rho kinase did not modulate cytoskeletal changes through JNK activation. These data demonstrate that RhoA/Rho kinase pathway is rapidly activated by TNF‐α and regulates several downstream responses that include JNK activation, cytoskeletal changes and increases in permeability. Supported by NIH HL070009.

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“…In mice, several lines of evidence have shown the involvement of IL-6 in neutrophil recruitment in acute inflammatory diseases such as pneumonia 3,4 . Another possibility is that IL-6 is involved in neutrophil apoptosis, although further studies are needed to clarify the mechanism of IL-6-induced severe neutropenia 5 .…”

Section: To the Editormentioning

confidence: 99%