Cytokine expression in bronchial biopsies of cystic fibrosis patients with and without acute exacerbation

Wojnarowski, Claudia; Frischer, Thomas; Hofbauer, Elisabeth; Grabner, Claudia; Mosgoeller, Wilhelm; Eichler, Irmgard; Ziesche, Rolf

doi:10.1183/09031936.99.14511369

Cited by 79 publications

(62 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As shown here, chloroquine, furin inhibitors, or TGF-β blocking antibodies normalize collagen production, confirming the cascade depicted in Figure 7. TGF-β has been detected in CF specimens, including histological preparations (42) and bronchoalveolar lavage fluid (BALF) (43). A recent direct measurement of TGF-β 1 in BALF from 43 CF patients (43) found a correlation between TGF-β 1 in BALF and reticular basement membrane thickness (RBMT) in endobronchial biopsies in CF.…”

Section: Discussionmentioning

confidence: 99%

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Ornatowski¹,

Poschet²,

Perkett³

et al. 2007

J. Clin. Invest.

View full text Add to dashboard Cite

Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-β and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF.

show abstract

Section: Discussionmentioning

confidence: 99%

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Ornatowski¹,

Poschet²,

Perkett³

et al. 2007

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…In animals with artificial cochlear inflammation TNF-α induced an amplification of the immune response leading to an increase of inflammation and disease progression (28). In patients with acute exacerbation of cystic fibrosis, the secretion of TNF-α was significantly lower in comparison with healthy controls and returned to normal secretion after treatment (24,25,30). In the airways of CF patients significantly elevated levels of circulating proinflammatory cytokines, in particular TNF-α have been reported (24).…”

Section: Oral Submucosis Fibrosis -(S) +(S) +(S)mentioning

confidence: 99%

“…In the airway epithelium of CF patients increased levels of IFN-γ mRNA should be verified (30). The mRNA of both IFN-γ and IL-6 mRNA were elevated for liver specimens of a transgenic mouse model for chronic hepatitis C-virus liver disease.…”

Section: Oral Submucosis Fibrosis -(S) +(S) +(S)mentioning

confidence: 99%

Significant alterations of serum cytokine levels in patients with Peyronie's disease

et al. 2008

View full text Add to dashboard Cite

Objective: To determine the expression of the cytokines transforming growth factor-β1 (TGF-β1), interferon-γ (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum from patients with Peyronie's disease (PD) compared to healthy controls. Materials and Methods: Ninety-one consecutive PD patients aged 20 -74 years were included in this study. All patients were diagnosed with symptomatic PD for the first time and had a palpable penile plaque. The patients previously had the disease for 6 -72 months. None of the patients had a severe infectious disease or known systemic illness. For cytokine analyses, peripheral venous blood samples were obtained before treatment. Fifty healthy male blood donors aged 22 -64 years served as the control group. TGF-β1, IFN-γ, Il-6, and TNF-α were analyzed quantitatively with commercial immunoassays. Results: Mean cytokine levels in serum from patients were increased for TGF-β1 and IFN-γ compared to healthy controls. The difference for TGF-β1 was considered statistically significant (p < 0.001). IL-6 was not detectable in PD patients (p < 0.01) and TNF-α was decreased (p < 0.0001). Conclusion:The significantly elevated serum level of the profibrotic TGF-β1 cytokine underscores the effect of cytokines in the pathophysiology of PD. The significantly decreased TNF-α serum level suggested no acute immunomodulatory process. Therefore, the relevance for therapeutic administration of TNF-α should be further investigated. Quantification of TGF-β1 in serum of PD patients provides a possible diagnostic tool and target for therapy. The data on altered cytokine levels in PD patients also provide a new understanding for etiopathogenesis of PD, which warrants further investigation.

show abstract

“…For example, as mentioned above, the CF airway is characterized not only by high levels of IL-8 but also by high levels of TNF␣, IL-6, and many other potent proinflammatory analytes (5)(6)(7). Furthermore, many of the CF-specific proinflammatory processes have been associated with up-regulation of both TNF␣/NFB signaling (13,14) and TGF␤-1 signaling (15). Thus, the CFTR mutation appears to target a proinflammatory regulatory mechanism with simultaneous deleterious effects on many proinflammatory genes.…”

mentioning

confidence: 99%

Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Bhattacharyya

Balakathiresan²,

Dalgard

et al. 2011

Journal of Biological Chemistry

193

167

View full text Add to dashboard Cite

Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive. We hypothesized that specific microRNAs (miRNAs) might mediate this linkage. To identify the potential link, we screened an miRNA library for differential expression in ⌬F508-CFTR and wild type CFTR lung epithelial cell lines. Of 22 differentially and significantly expressed miRNAs, we found that expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells in culture, compared with control IB3-1/S9 cells. Clinically, miR-155 was also highly expressed in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. We report here that high levels of miR-155 specifically reduced levels of SHIP1, thereby promoting PI3K/Akt activation. However, overexpressing SHIP1 or inhibition of PI3K in CF cells suppressed IL-8 expression. Finally, we found that phospho-Akt levels were elevated in CF lung epithelial cells and were specifically lowered by either antagomir-155 or elevated expression of SHIP1. We therefore suggest that elevated miR-155 contributes to the proinflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway. These data suggest that miR-155 may play an important role in the activation of IL-8-dependent inflammation in CF.

show abstract

Cytokine expression in bronchial biopsies of cystic fibrosis patients with and without acute exacerbation

Cited by 79 publications

References 24 publications

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Significant alterations of serum cytokine levels in patients with Peyronie's disease

Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8

Contact Info

Product

Resources

About