Laboratory of Immunology, Department of Biomedical Sciences / Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
J Exp Med. 2011 Aug 1;208(8):1707-19. doi: 10.1084/jem.20101457. Epub 2011 Jul 11.
Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)-dependent manner. This response represents a key step in the differentiation of IL-17-producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention.
肺纤维化是一种潜在的危及生命的疾病，可能由显性或无症状的炎症反应引起。然而，组织损伤如何转化为炎症和随后的纤维化的精确机制仍有待确定。在这里，我们表明，在肺损伤模型中，博来霉素以转谷氨酰胺酶 2（TG2）依赖的方式诱导上皮细胞分泌白细胞介素 6（IL-6）。这种反应代表了 IL-17 产生的 T 细胞分化和随后肺部炎症放大的关键步骤。上皮细胞，而不是炎症细胞，在骨髓嵌合体中证实了 TG2 的关键作用；与野生型小鼠相比，无论骨髓细胞表型如何，缺乏 TG2 的嵌合体小鼠显示出炎症和纤维化减少。因此，上皮细胞 TG2 似乎是非传染性肺损伤后炎症的关键诱导物。我们进一步表明，成纤维细胞衍生的 TG2 在转化生长因子-β的下游作用对于纤维发生的效应阶段也很重要。因此，TG2 代表了一个有趣的治疗干预的潜在靶点。
