Center for Immunobiology and Pulmonary Division, Department of Medicine.
Department of Pathology.
FASEB J. 2014 Oct;28(10):4223-34. doi: 10.1096/fj.13-247650. Epub 2014 Jun 23.
The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor β1 (TGF-β1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-β1 in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-β1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-β1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-β), and whereas TGF-β1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a-/C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-β1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-β1 expression
上皮细胞补体抑制蛋白 (CIP) 簇分化抗原 46 和 55 (CD46 和 CD55) 调节特发性肺纤维化 (IPF) 中循环免疫复合物介导的补体激活。我们之前的研究表明，白细胞介素 17A (IL-17A) 通过转化生长因子 β1 (TGF-β1) 介导上皮损伤，并下调 CIP。在本研究中，我们研究了 TGF-β1 在 IPF 发病机制中补体激活介导的气道上皮损伤中的机制作用。我们观察到与正常肺相比，IPF 肺中的上皮 CIP 表达降低，同时局部和全身的补体成分 3a 和 5a (C3a 和 C5a) 水平升高。在正常的原代人小气道上皮细胞 (SAECs) 中用 TGF-β1 (10 ng/ml)、C3a 或 C5a (100 nM) 处理时，我们观察到 CIP 丢失和多聚 (ADP-核糖) 聚合酶 (PARP) 激活增加 [也通过 CD46/CD55 的 RNA 干扰 (RNAi) 观察到]。TGF-β1 介导的 CIP 丢失和 Snail 诱导 [SNAI1；E-钙黏蛋白 (E-CAD) 的转录抑制因子] 通过抑制丝裂原活化蛋白激酶 (p38MAPK；SB203580) 和 SNAI1 的 RNAi 沉默而被阻断。C3a 和 C5a 介导的 CIP 丢失也被 p38MAPK 抑制阻断。虽然 C3a 上调 TGFb 转录物，但 C3a 和 C5a 均下调 SMAD7( TGF-β 的负调节剂)，而 TGF-β1 诱导 C3a/C5a 受体 (C3aR/C5aR) 表达，药理学 C3aR/C5aR 抑制可防止 C3a/C5a 介导的 CIP 丢失。综上所述，我们的结果表明，由于 TGF-β1 诱导的 CIP 丢失导致补体激活，从而下调 CIP 并诱导 TGF-β1 表达，IPF 中的上皮损伤可能会被集体放大。
