Tissue transglutaminase activation modulates inflammation in cystic fibrosis via PPARgamma down-regulation.
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 gamma and increase of the classic parameters of inflammation, such as TNF-alpha, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-gamma 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.
Maiuri
Luigi
L
European Institute for Cystic Fibrosis Research, San Raffaele Scientific Institute, Milan, Italy
Luciani
Alessandro
A
Giardino
Ida
I
Raia
Valeria
V
Villella
Valeria R
VR
D'Apolito
Maria
M
Pettoello-Mantovani
Massimo
M
Guido
Stefano
S
Ciacci
Carolina
C
Cimmino
Mariano
M
Cexus
Olivier N
ON
Londei
Marco
M
Quaratino
Sonia
S
D002460:Cell Line; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D025801:Ubiquitin / Q000276:immunology / Q000378:metabolism
C505032:CFTR protein, human; D016207:Cytokines; D047495:PPAR gamma; D025801:Ubiquitin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D019204:GTP-Binding Proteins