Maiuri Luigi, Luciani Alessandro, Giardino Ida, Raia Valeria, Villella Valeria R, D'Apolito Maria, Pettoello-Mantovani Massimo, Guido Stefano, Ciacci Carolina, Cimmino Mariano, Cexus Olivier N, Londei Marco, Quaratino Sonia
European Institute for Cystic Fibrosis Research, San Raffaele Scientific Institute, Milan, Italy
J Immunol. 2008 Jun 1;180(11):7697-705. doi: 10.4049/jimmunol.180.11.7697.
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.
囊性纤维化（CF）是白种人中最常见的危及生命的遗传性疾病，由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起，其特征为气道慢性炎症和肺部感染。炎症反应并非继发于肺部感染。事实上，多项研究表明，无论是否存在细菌感染，CF组织中的促炎活性都会增加，因为在无菌条件下培养的CFTR缺陷细胞系中也观察到了类似的炎症现象。尽管最近的研究表明CF气道上皮细胞可自发启动炎症级联反应，但我们仍不清楚这种炎症反应增加所涉及的分子机制。在本研究中，为了解这些机制，我们调查了CF患者和对照者鼻息肉黏膜外植体、CFTR缺陷的IB3 - 1支气管上皮细胞、C38等基因CFTR校正细胞以及16HBE正常支气管上皮细胞系的体外培养情况。我们发现，缺陷的CFTR会导致组织转谷氨酰胺酶（TG2）在组织和细胞系中显著上调。TG2活性增加会导致抗炎性过氧化物酶体增殖物激活受体γ发生功能性隔离，并增加炎症的经典参数，如肿瘤坏死因子-α、酪氨酸磷酸化和丝裂原活化蛋白激酶。特异性抑制TG2能够恢复过氧化物酶体增殖物激活受体-γ的正常水平，并减轻CF组织和CFTR缺陷细胞中的炎症。我们的研究结果突出了TG2在CF炎症机制途径中未曾预料到的核心作用，也为慢性炎症性疾病患者开辟了可能的新一波治疗方法。
