Cytokine Secretion by Cystic Fibrosis Airway Epithelial Cells

Becker, Marie N.; Sauer, Mariam S.; Muhlebach, Marianne S.; Hirsh, Andrew J.; Wu, Qi; Verghese, Margrith W.; Randell, Scott H.

doi:10.1164/rccm.200207-765oc

Cited by 124 publications

(115 citation statements)

References 37 publications

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“…However, conflicting results have been reported on whether CF airways undergo proinflammatory response in the absence of bacterial infections (14 -16). Several studies have shown that both cytokine profile secretion and NF-B activation are similar in CF and normal cells (17,18). However, mounting evidence suggests that inflammation may occur before infection, and CFTR-defective cells have an intrinsically proinflammatory phenotype (19 -23).…”

Section: Ystic Fibrosis (Cf)mentioning

confidence: 99%

SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation

Luciani

Villella

Vasaturo

et al. 2009

The Journal of Immunology

102

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Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by chronic bacterial lung infections and inflammation, and we have previously reported that tissue transglutaminase (TG2), a multifunctional enzyme critical to several diseases, is constitutively up-regulated in CF airways and drives chronic inflammation. Here, we demonstrate that the generation of an oxidative stress induced by CFTR-defective function leads to protein inhibitor of activated STAT (PIAS)y-mediated TG2 SUMOylation and inhibits TG2 ubiquitination and proteasome degradation, leading to sustained TG2 activation. This prevents peroxisome proliferator-activated receptor (PPAR)γ and IkBα SUMOylation, leading to NF-κB activation and to an uncontrolled inflammatory response. Cellular homeostasis can be restored by small ubiquitin-like modifier (SUMO)-1 or PIASy gene silencing, which induce TG2 ubiquitination and proteasome degradation, restore PPARγ SUMOylation, and prevent IkBα cross-linking and degradation, thus switching off inflammation. Manganese superoxide dismutase overexpression as well as the treatment with the synthetic superoxide dismutase mimetic EUK-134 control PIASy-TG2 interaction and TG2 SUMOylation. TG2 inhibition switches off inflammation in vitro as well as in vivo in a homozygous F508del-CFTR mouse model. Thus, TG2 may function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or degradation. Targeting TG2-SUMO interactions might represent a new option to control disease evolution in CF patients as well as in other chronic inflammatory diseases, neurodegenerative pathologies, and cancer.

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Section: Ystic Fibrosis (Cf)mentioning

confidence: 99%

SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation

Luciani

Villella

Vasaturo

et al. 2009

The Journal of Immunology

102

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“…These cultures, derived from both animal and adult human cells, have been instrumental in increasing our knowledge of epithelial cell physiology (10) and responses to insults such as bacterial and viral infection (11,12). The establishment of a novel welldifferentiated primary bronchial epithelial cell (WD-PBEC) model using epithelial cells from children would therefore be useful in addressing these issues in childhood asthma.…”

mentioning

confidence: 99%

A 3-D Well-Differentiated Model of Pediatric Bronchial Epithelium Demonstrates Unstimulated Morphological Differences Between Asthmatic and Nonasthmatic Cells

et al. 2010

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There is a need for reproducible and effective models of pediatric bronchial epithelium to study disease states such as asthma. We aimed to develop, characterize, and differentiate an effective, an efficient, and a reliable three-dimensional model of pediatric bronchial epithelium to test the hypothesis that children with asthma differ in their epithelial morphologic phenotype when compared with nonasthmatic children. Primary cell cultures from both asthmatic and nonasthmatic children were grown and differentiated at the air-liquid interface for 28 d. Tight junction formation, MUC5AC secretion, IL-8, IL-6, prostaglandin E2 production, and the percentage of goblet and ciliated cells in culture were assessed. Well-differentiated, multilayered, columnar epithelium containing both ciliated and goblet cells from asthmatic and nonasthmatic subjects were generated. All cultures demonstrated tight junction formation at the apical surface and exhibited mucus production and secretion. Asthmatic and nonasthmatic cultures secreted similar quantities of IL-8, IL-6, and prostaglandin E2. Cultures developed from asthmatic children contained considerably more goblet cells and fewer ciliated cells compared with those from nonasthmatic children. A well-differentiated model of pediatric epithelium has been developed that will be useful for more in vivo like study of the mechanisms at play during asthma. (Pediatr Res 67: 17-22, 2010)

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“…Agonist stimulation of TLR2 causes RE cells to produce IL-6 and IL-8 (16,44), suggesting that TLR2-mediated signals in RE cells regulate the immune response by regulating the production of various chemokines and cytokines. In our experiments, treatment of RE cells with TLR2 agonists induced the production of MIP-1a, MCP-1, and IP-10, stimulating the recruitment of inflammatory cells into the lungs during BIPF.…”

Section: Discussionmentioning

confidence: 99%

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

Kim

Akira

et al. 2011

The Journal of Immunology

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Idiopathic pulmonary fibrosis is a fatal disease characterized by progressive destruction of the lung. Although TLR2 bridges innate and adaptive immunity by sensing tissue damage, its role in pulmonary fibrosis remains unclear. To address this issue, TLR2−/− and WT mice were examined for bleomycin-induced pulmonary fibrosis (BIPF). Flow cytometric and immunohistochemical analysis revealed that TLR2 expression in bronchial epithelial and immune cells of the lungs was upregulated in WT mice during BIPF. Levels of IL-27, TGF-β, chemokines, and hydroxyproline were lower in lungs of TLR2−/− mice than in those of WT mice, but IL-17 levels were higher in TLR2−/− mice. In in vivo experiments using bone marrow-chimeric mice, TLR2 expression on respiratory epithelial cells, rather than immune cells, induced IL-27 and chemokine production in the lungs, further stimulating BIPF. This effect of TLR2 depended on IRF complexes and MyD88. BIPF was more severe in IL-17A−/− mice and in TLR2−/− mice treated with anti–IL-17 mAb than in TLR2−/− and WT mice. Furthermore, IL-27 blockade in WT mice reduced hydroxyproline levels by enhancing IL-17 production, whereas the treatment of TLR2−/− mice with a chemokine mixture increased hydroxyproline levels by recruiting inflammatory cells into the lungs. TLR2 signaling promotes BIPF by inducing IL-27 and chemokine production by respiratory epithelial cells, thereby inhibiting IL-17 production and recruiting inflammatory cells into the lungs.

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Cytokine Secretion by Cystic Fibrosis Airway Epithelial Cells

Cited by 124 publications

References 37 publications

SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation

SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation

A 3-D Well-Differentiated Model of Pediatric Bronchial Epithelium Demonstrates Unstimulated Morphological Differences Between Asthmatic and Nonasthmatic Cells

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

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