Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling
Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling
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DOI：
10.1074/jbc.m506770200
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发表时间：
2006-03-24
影响因子：
4.8
通讯作者：
Lee, CG
中科院分区：
文献类型：
--
作者：
Cho, SJ;Kang, MJ;Lee, CG
IL-13是Th2炎症部位炎症和组织重塑的重要刺激因子，在多种人类疾病的发病机制中起着关键作用。我们假设，普遍存在的转录因子早期生长反应-1(Egr-1)在IL-13诱导的组织反应中发挥关键作用。为了验证这一假设，我们比较了野生型和转基因小鼠肺中Egr-1和相关部分的表达，在转基因小鼠中，IL-13以肺特有的方式过度表达。我们同时研究了Egr-1零突变对转基因IL-13的组织效应的影响。这些研究表明，IL-13通过ERK1/2非依赖的STAT6依赖途径刺激Egr-1(S)。他们还证明，在携带野生型Egr-1基因的小鼠中，IL-13是富含嗜酸性粒细胞和单核细胞的炎症、肺泡重塑和组织纤维化的有效刺激因素，并且这些变化在缺少Egr-1的情况下得到改善。最后，他们通过证明IL-13刺激特定的CC和CXC趋化因子(MIP-1α/CCL-3、MIP-1β/CCL-4、MIP-2/CXCL2/3、MCP-1/CCL-2、MCP-2/CCL-8、MCP-3/CCL-7、MCP-5/CCL-12、KC/CXCL-1和Lix/CXCL-5)、基质金属蛋白酶-9、金属蛋白酶组织抑制因子-1和细胞凋亡调节因子(caspase-3、-6、-8、-8、cCL-7、MCP-5/CCL-12、KC/CXCL-1和Lix/CXCL-5)、基质金属蛋白酶-9、金属蛋白酶组织抑制因子-1和细胞凋亡调节因子(caspase-3、-6、-8、-8、和Bax)，并通过Egr-1依赖的途径激活转化生长因子-β(1)和肺caspase。这些研究表明，Egr-1在IL-13诱导的炎症和重塑反应的发病机制中起关键作用。
IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties in lungs from wild type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil- and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1 alpha/CCL-3, MIP-1 beta/CCL-4, MIP-2/CXCL2/3, MCP-1/ CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators(caspase-3,- 6,- 8, and- 9 and Bax) and activates transforming growth factor-beta(1) and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses.