IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis
IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis
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DOI：
10.1038/nm1332
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发表时间：
2006-01-01
期刊：
影响因子：
82.9
通讯作者：
Kitani, A
中科院分区：
文献类型：
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作者：
Fichtner-Feigl, S;Strober, W;Kitani, A
白细胞介素（IL）-13是许多慢性感染性和自身免疫性疾病中纤维化的主要诱导物。在对这种诱导的潜在机制的研究中，我们发现IL-13通过两个阶段的过程诱导巨噬细胞中的转化生长因子（TGF）-β（1），首先是诱导以前被认为仅作为诱饵受体的受体IL-13 R α（2）。这种诱导需要IL-13（或IL-4）和肿瘤坏死因子（TNF）-α。第二，它涉及IL-13信号通过IL-13 R α（2）激活含有c-jun和Fra-2的AP-1变体，然后激活TGFB 1启动子。在体内，我们发现，在恶唑酮诱导的结肠炎中，IL-13 R α 2表达的抑制减少了TGF-β 1的产生，而在博莱霉素诱导的肺纤维化中，IL-13 Ra 2表达的抑制、IL-13 Ra 2基因沉默或IL-13 R α 2信号传导的阻断导致TGF-β 1的产生和胶原沉积显著下调。这些数据表明，IL-13 R α（2）信号在长期炎症是一个重要的治疗目标，为预防TGF-β（1）介导的纤维化。
Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13R alpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13R alpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13R alpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ra2 expression, Il13ra2 gene silencing or blockade of IL-13R alpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13R alpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.