The IKK-2/IκBα/NF-κB pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts -: A critical link to dermatitis in IκBα-deficient mice
The IKK-2/IκBα/NF-κB pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts -: A critical link to dermatitis in IκBα-deficient mice
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DOI：
10.1074/jbc.m109358200
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发表时间：
2002-01-11
影响因子：
4.8
通讯作者：
Wirth, T
中科院分区：
文献类型：
--
作者：
Huber, MA;Denk, A;Wirth, T
含有IKK-2的IkappaB激酶（IKK）复合物诱导IkappaB蛋白磷酸化以及随后IkappaB蛋白的降解是NF-kappaB活化的先决条件，导致多种促炎靶基因的刺激。C-C趋化因子eotaxin-1是一种有效的嗜酸性粒细胞和Th2淋巴细胞的趋化剂，可能在特应性皮炎的发病过程中发挥重要作用，并通过与其受体CCR3结合而起作用。为了研究NF-kappaB信号在这些基因调控中的作用，我们在小鼠NIH3T3成纤维细胞中稳定表达了ikappabα的跨显性突变体和IKK-2的组成型活性突变体。跨显性IkappaBalpha突变体完全抑制了tnf - α介导的eotaxin-1和CCR3的诱导，而组成型活性IKK-2的表达足以在缺乏tnf - α的情况下驱动这两个基因的几乎完全表达。此外，我们观察到以广泛皮炎为特征的ikappabα缺陷小鼠皮肤中CCR3和eotaxin- 1蛋白表达水平升高。最后，使用来自ikappabalpha缺陷小鼠的真皮成纤维细胞，我们观察到CCR3和eotaxin-1 mRNA水平的基础表达升高，tnf - α的诱导性增强，tnf - α退出后CCR3和eotaxin-1 mRNA水平的下调减弱。这些结果表明IKK-2/IkappaBalpha/NF-kappaB通路对成纤维细胞中CCR3和eotaxin-1的表达起关键作用，并提示与特应性皮炎的发病机制有关。
Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-l protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.