Expression of Functional Toll-Like Receptor-2 and -4 on Alveolar Epithelial Cells

Armstrong, Lynne; Medford, Andrew R L; Uppington, Kay M.; Robertson, J. F. R.; Witherden, Ian R.; Tetley, Teresa D.; Millar, Ann

doi:10.1165/rcmb.2004-0078oc

Cited by 197 publications

(168 citation statements)

References 27 publications

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“…TLR2 is expressed on the surface of type II alveolar epithelial cells (52,53) and has been shown to permit S. pneumoniae-induced NF-B activation in this cell type (54,55). Interestingly, SP3 failed to induce RelA nuclear translocation in our current studies, regardless of dose or timing.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, murine AM have been shown to produce TNF-␣ in response to type III pneumococcus in a TLR2-dependent fashion (72). The mechanism through which AM and not MLE-15 cells respond to SP3 remains unknown but may be attributable to basal differences in TLR2 expression (52). Alternatively, it is possible that epithelial cells are less responsive to pneumolysin, which signals through TLR4 (73), and/or other pathogen-associated molecular patterns that are recognized by AM.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…AECs have been shown to express TLR2 and TLR4 and release IL-8 in response to Streptococcus pneumoniae, lipoteichoic acid, and lipopolysaccharide (99,100). Furthermore, TLR9 activation in bronchial epithelial cells has been shown to potentiate IL-8 release from bronchial epithelial cells (101).…”

Section: Tlr-dependent Signaling In the Pulmonary Epithelium: A Role mentioning

confidence: 99%

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Gribar

Richardson

Sodhi

et al. 2008

Mol Med

142

109

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Diseases of mucosal inflammation represent important causes of morbidity and mortality, and have led to intense research efforts to understand the factors that lead to their development. It is well accepted that a breakdown of the normally impermeant epithelial barrier of the intestine, the lung, and the kidney is associated with the development of inflammatory disease in these organs, yet significant controversy exists as to how this breakdown actually occurs, and how such a breakdown may lead to inflammation. In this regard, much work has focused upon the role of the epithelium as an "innocent bystander," a target of a leukocyte-mediated inflammatory cascade that leads to its destruction in the mucosal inflammatory process. However, recent evidence from a variety of laboratories indicates that the epithelium is not merely a passive component in the steps that lead to mucosal inflammation, but is a central participant in the process. In addressing this controversy, we and others have determined that epithelial cells express Toll-like receptors (TLRs) of the innate immune system, and that activation of TLRs by endogenous and exogenous ligands may play a central role in determining the balance between a state of "mucosal homeostasis," as is required for optimal organ function, and "mucosal injury," leading to mucosal inflammation and barrier breakdown. In particular, activation of TLRs within intestinal epithelial cells leads to the development of cellular injury and impairment in mucosal repair in the pathogenesis of intestinal inflammation, while activation of TLRs in the lung and kidney may participate in the development of pneumonitis and nephritis respectively. Recent work in support of these concepts is extensively reviewed, while essential areas of further study that are required to determine the significance of epithelial TLR signaling during states of health and disease are outlined.

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“…Presence of both proteins in bronchoalveolar lavage (BAL) can serve as a good marker for lung injury. LPS can stimulate TLR4 expressed in alveolar type II cells (Armstrong et al, 2004). Both TNFa and LPS have been reported to regulate CC10 expression (Yao et al, 1998;Arsalane et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

et al. 2011

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We have previously shown that tumor necrosis factor (TNF)a produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b þ TLR4 þ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4 þ Clara cells could be derived from bone marrow. SAA3-induced TNFa expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNFa in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin.

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Expression of Functional Toll-Like Receptor-2 and -4 on Alveolar Epithelial Cells

Cited by 197 publications

References 27 publications

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

Functions and Regulation of NF-κB RelA during Pneumococcal Pneumonia

No Longer an Innocent Bystander: Epithelial Toll-Like Receptor Signaling in the Development of Mucosal Inflammation

Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

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