Tissue Transglutaminase Activation Modulates Inflammation in Cystic Fibrosis via PPARγ Down-Regulation1 (original) (raw)
Journal Article
European Institute for Cystic Fibrosis Research, San Raffaele Scientific Institute
,
Milan
,
Italy
Institute of Pediatrics, University of Foggia
,
Foggia
,
Italy
Address correspondence and reprint requests to Luigi Maiuri, European Institute for Cystic Fibrosis Research, San Raffaele Scientific Institute, via Olgettina 58, 20132, Milan, Italy. E-mail address: [email protected]
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Institute of Pediatrics, University of Foggia
,
Foggia
,
Italy
Department of Experimental Medicine, University Federico II
,
Naples
,
Italy
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Department of Laboratory Medicine, University of Foggia
,
Foggia
,
Italy
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Department of Pediatrics, University Federico II
,
Naples
,
Italy
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Department of Chemical Engineering, University Federico II
,
Naples
,
Italy
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Institute of Pediatrics, University of Foggia
,
Foggia
,
Italy
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Massimo Pettoello-Mantovani
Institute of Pediatrics, University of Foggia
,
Foggia
,
Italy
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Department of Chemical Engineering, University Federico II
,
Naples
,
Italy
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Department of Experimental Medicine, University Federico II
,
Naples
,
Italy
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Department of Otolaryngology, University Federico II
,
Naples
,
Italy
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Received:
08 January 2008
Cite
Luigi Maiuri, Alessandro Luciani, Ida Giardino, Valeria Raia, Valeria R Villella, Maria D'Apolito, Massimo Pettoello-Mantovani, Stefano Guido, Carolina Ciacci, Mariano Cimmino, Olivier N Cexus, Marco Londei, Sonia Quaratino, Tissue Transglutaminase Activation Modulates Inflammation in Cystic Fibrosis via PPARγ Down-Regulation, The Journal of Immunology, Volume 180, Issue 11, June 2008, Pages 7697–7705, https://doi.org/10.4049/jimmunol.180.11.7697
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Abstract
Cystic fibrosis (CF), the most common life-threatening inherited disease in Caucasians, is due to mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by airways chronic inflammation and pulmonary infections. The inflammatory response is not secondary to the pulmonary infections. Indeed, several studies have shown an increased proinflammatory activity in the CF tissues, regardless of bacterial infections, because inflammation is similarly observed in CFTR-defective cell lines kept in sterile conditions. Despite recent studies that have indicated that CF airway epithelial cells can spontaneously initiate the inflammatory cascade, we still do not have a clear insight of the molecular mechanisms involved in this increased inflammatory response. In this study, to understand these mechanisms, we investigated ex vivo cultures of nasal polyp mucosal explants of CF patients and controls, CFTR-defective IB3-1 bronchial epithelial cells, C38 isogenic CFTR corrected, and 16HBE normal bronchial epithelial cell lines. We have shown that a defective CFTR induces a remarkable up-regulation of tissue transglutaminase (TG2) in both tissues and cell lines. The increased TG2 activity leads to functional sequestration of the anti-inflammatory peroxisome proliferator-activated receptor γ and increase of the classic parameters of inflammation, such as TNF-α, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-γ and dampen down inflammation both in CF tissues and CFTR-defective cells. Our results highlight an unpredicted central role of TG2 in the mechanistic pathway of CF inflammation, also opening a possible new wave of therapies for sufferers of chronic inflammatory diseases.
Copyright © 2008 by The American Association of Immunologists
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