炎症因子在组织纤维化中介导组织型转谷氨酰胺酶的表达

Inflammatory Cytokine Mediated Expression of Tissue Transglutaminase in Tissue Fibrosis

摘要:

组织型转谷氨酰胺酶（tissue transglutaminase, tTG, tGM2, EC2.3.2.13）是蛋白质转谷氨酰胺酶（protein-glutamine γ-glutamyltransferases）家族中的一员，具有催化谷氨酰胺残基与赖氨酸残基的缩合反应，形成异肽键，使两条肽链发生交联。其外分泌型的tTG参与细胞外基质（extracellular matrix, ECM)的交联。另一方面，组织纤维化（tissue fibrosis)是大面积损伤／长期感染导致的异常修复结果；纤维化也与肿瘤的发生相关。在细胞水平上，纤维化是由肌成纤维细胞(myofibroblasts)以及其细胞外基质的大量积累，交联导致的结果。该研究的目的是测定tTG的表达与组织纤维化的相关性。第一，在肝硬化病人的标本中，我们发现tTG和α-平滑肌肌动蛋白（alpha-smooth muscle actin，alpha-SMA)共位表达，表明与肝星状细胞（hepatic stellate cells)的激活／转分化有关，与肝硬化的程度相关。 第二，烧伤病人的增生性瘢痕皮肤中我们发现tTG含量也相对于正常皮肤增加明显，并且分布于细胞外胶原蛋白之中，于alpha-SMA阳性细胞的周围。第三，经体外星状细胞实验，我们发现白细胞介素1(interleukin 1, IL-1)能够诱导肝星状细胞在蛋白水平和mRNA水平表达tTG。同样，肿瘤坏死因子α（Tumor necrosis factor alpha，TNF-α）也能诱导表皮细胞（Hacat）表达tTG。因此，我们的研究表明在组织损伤过程中，炎症反应可能引发细胞外基质的交联，促进纤维化。

Abstract:

Tissue transglutaminase (tTG) is an enzyme (EC2.3.2.13) being able to crosslink polypeptides into iso-peptide bonds. Fibrosis is mediated by myofibroblasts, which produce extracellular matrix (ECM) and generate wound contraction. Here we assessed the expression of tGT in human fibrotic tissues, and addressed how tGT is induced in fibrotic tissues. Through immunofluorescent staining we found that exclusive expression of tTG in fibrotic septa of human cirrhotic liver, co-localized with the alpha-smooth muscle (alpha-SMA) positive cells, implying hepatic stellate cells for tTG expression. Absence from normal skin, tTG was highly expressed in the human hypertrophic scar, which was also intimately associated with the alpha-SMA positive cells. In vitro experiment showed that interleukin-1 could induce tTG expression by rat primary hepatic stellate cells (HSCs). Likewise, TNF-α could induce tTG expression by skin epithelial cells. Thus, our work indicates that inflammatory cytokines may play a critical role in induction of tTG in fibrosis formation.