Diverse Pseudomonas aeruginosa gene products stimulate respiratory epithelial cells to produce interleukin-8.

DiMango, Emily; Zar, Heather J.; Bryan, Ruth; Prince, Alice

doi:10.1172/jci118275

Cited by 399 publications

(321 citation statements)

References 39 publications

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“…L, airway lumen; SG, submucosal glands. lin) (17), and PAO͞NP (deficient in production of pilin) (13). That these media were as potent as that of wild type essentially excluded a role for the mutant gene products (data not shown).…”

Section: Resultsmentioning

confidence: 93%

“…We next addressed the question of which components of P. aeruginosa are responsible for MUC 2 up-regulation. Via the screening of P. aeruginosa mutants, it has been found that diverse products of this organism can affect host gene expression (13). We assessed the role of some of these in MUC 2 up-regulation by testing the potency of culture supernatant from bacterial mutants PAOR1 (deficient in production of the P. aeruginosa autoinducer, elastase, alkaline protease, and neuraminidase) (14-16), AK1152 (deficient in production of pilin and flagel- FIG.…”

Section: Resultsmentioning

confidence: 99%

“…Previously reported data revealed that CFTR mutant epithelial cells are hypersusceptible to some biological effects of P. aeruginosa (13). To examine the possibility that this is also true of MUC 2 transcriptional up-regulation, we compared the magnitude of P. aeruginosa responses in CFTR mutant cells that had vs. those that had not been complemented by transfection with wild-type CFTR expression plasmid.…”

Section: Fig 5 Inhibition Of P Aeruginosa-induced Muc 2 Up-regulationmentioning

confidence: 99%

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Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease

Dohrman

Gallup

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

268

215

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An unresolved question in cystic fibrosis (CF) research is how mutations of the CF transmembrane conductance regulator, a Cl ion channel, cause airway mucus obstruction leading to fatal lung disease. Recent evidence has linked the CF transmembrane conductance regulator mutation to the onset and persistence of Pseudomonas aeruginosa infection in the airways, and here we provide evidence directly linking P. aeruginosa infection to mucus overproduction. We show that P. aeruginosa lipopolysaccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this effect is blocked by the tyrosine kinase inhibitors genistein and tyrphostin AG 126. These findings improve our understanding of CF pathogenesis and suggest that the attenuation of mucin production by lipopolysaccharide antagonists and tyrosine kinase inhibitors could reduce morbidity and mortality in this disease.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Fig 5 Inhibition Of P Aeruginosa-induced Muc 2 Up-regulationmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease

Dohrman

Gallup

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

268

215

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“…Secretion of IL-8, TNF-and other proinflammatory cytokines by airway epithelial cells and lung macrophages with accumulation and activation of neutrophils in the CF airways may underlie the early pathogenesis of CF lung disease [58,59,63,64]. This inflammatory process is greatly magnified by epithelial cell IL-8 production stimulated by products of colonizing bacterial pathogens and neutrophils [65,66]. Bonfield et al reported a selective reduction in IL-10 production by CF bronchial epithelial cells and reduced IL-10 levels in CF bronchoalveolar lavage fluid [67,68].…”

Section: Discussionmentioning

confidence: 99%

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Moss¹,

Bocian²,

Hsu³

et al. 1996

Clinical and Experimental Immunology

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Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. Non‐transformed, antigen‐responsive CD4+ T cells cloned from healthy controls and CF patients homozygous or heterozygous for the δF508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF patients displayed equivalent Ca2+‐mediated Cl− current; however, TCC from patients with CF but not controls displayed defective cAMP‐mediated Cl− current. Although CF‐derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted ≈ 45% less IL‐10 compared with control TCC after activation with concanavalin A (Con A) (624 ± 101 versus 1564 ± 401 pg/ml per 106 cells, respectively; P = 0.04) or anti‐CD3/phorbol ester (5148 ± 1634 versus 11 788 ± 2390 pg/ml; P = 0.05). This difference was independent of atopy. Secretion of interferon‐gamma, IL‐2, and IL‐4 was comparable in CF and control TCC after both forms of activation, while IL‐5 was reduced in CF TCC following anti‐CD3/phorbol myristate acetate (PMA) but not after Con A. We conclude that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL‐10 secretion after polyclonal activation. It is possible that disruption of IL‐10‐mediated anti‐inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.

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“…2,3 Persistent bacterial colonisation, specifically by Pseudomonas aeruginosa (PA), is a characteristic feature of the CF lung, and may be the primary stimulus for neutrophil infiltration. 4 Thus, PA infection has been shown directly to stimulate secretion of the pro-inflammatory cytokine interleukin-8 (IL-8), a major neutrophil chemoattractant, in the airways, 5 which is produced by several cell types, including epithelial cells. Recently we have shown, that the degree of IL-8 stimulation in primary airway epithelial cells is directly related to the number of PA bound to the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory gene therapy directed at the airway epithelium

Griesenbach¹,

Scheid²,

Hillery³

et al. 2000

Gene Ther

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Diverse Pseudomonas aeruginosa gene products stimulate respiratory epithelial cells to produce interleukin-8.

Abstract: Respiratory epithelial cells play a crucial role in the inflammatory response during Pseudomonas aeruginosa infec-

Cited by 399 publications

References 39 publications

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease

Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Anti-inflammatory gene therapy directed at the airway epithelium

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