Interleukin-4 induces 15-lipoxygenase-1 expression in human orbital fibroblasts from patients with graves disease - Evidence for anatomic site-selective actions of Th2 cytokines
Interleukin-4 induces 15-lipoxygenase-1 expression in human orbital fibroblasts from patients with graves disease - Evidence for anatomic site-selective actions of Th2 cytokines
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DOI：
10.1074/jbc.m603484200
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发表时间：
2006-07-07
影响因子：
4.8
通讯作者：
Smith, Terry J.
中科院分区：
文献类型：
--
作者：
Chen, Beiling;Tsui, Shanli;Smith, Terry J.
眼眶成纤维细胞在Graves病中协调组织重塑，至少部分是因为它们对促炎细胞因子表现出过度反应。晚期眼眶疾病的标志是威胁视力的纤维化，其分子基础仍然不确定。我们在这里报告的Th 2细胞因子，白细胞介素（IL）-4和IL-13，可以诱导在这些细胞中的15-脂氧合酶-1（15-LOX-1）的表达，并在这样做上调生产15-羟基二十碳四烯酸。IL-4通过翻译前作用增加15-LOX-1蛋白水平。增加的稳态15-LOX-1 mRNA是独立的正在进行的蛋白质合成，并涉及非常温和的基因启动子活性增加。重要的是，IL-4显著增强了15-LOX-1转录物的稳定性，即定位于3 '-非翻译区的293-bp序列的活性。IL-4激活眼眶成纤维细胞中的Jak 2。中断通过该途径的信号传导，无论是与特定的化学抑制剂，AG 490，或通过短暂的干扰细胞与Jak 2显性负突变激酶，减弱15-LOX-1的诱导。干扰素γ，一种Th 1细胞因子，可以通过减弱IL-4依赖的mRNA稳定性来阻断这种诱导。15-LOX-1蛋白及其mRNA在IL-4处理的真皮成纤维细胞中检测不到，尽管细胞表面IL-4受体和磷酸化Jak 2和STAT 6的水平相当。我们的研究结果表明，眼眶结缔组织可能代表一个网站的本地化15-hydroxyyeicosatetraenoic酸产生细胞类型特异性15-LOX-1 mRNA的稳定IL-4。这些结果可能与眼眶格雷夫斯病的发病机制有关，格雷夫斯病是一种炎症性自身免疫性疾病，导致与Th 2应答相关的广泛纤维化。
Orbital fibroblasts orchestrate tissue remodeling in Graves disease, at least in part, because they exhibit exaggerated responses to proinflammatory cytokines. A hallmark of late stage orbital disease is vision-threatening fibrosis, the molecular basis of which remains uncertain. We report here that the Th2 cytokines, interleukin (IL)-4 and IL-13, can induce in these cells the expression of 15-lipoxygenase-1 (15-LOX-1) and in so doing up-regulate the production of 15-hydroxyeicosatetraenoic acid. IL-4 increases 15-LOX-1 protein levels through pretranslational actions. The increased steady-state 15-LOX-1 mRNA is independent of ongoing protein synthesis and involves very modestly increased gene promoter activity. Importantly, IL-4 substantially enhances 15-LOX-1 transcript stability, activity that localizes to a 293-bp sequence of the 3'-untranslated region. IL-4 activates Jak2 in orbital fibroblasts. Interrupting signaling through that pathway, either with the specific chemical inhibitor, AG490, or by transiently transfecting the cells with a Jak2 dominant negative mutant kinase, attenuates the 15-LOX-1 induction. Interferon gamma, a Th1 cytokine, could block this induction by attenuating IL-4-dependent mRNA stabilization. 15-LOX-1 protein and its mRNA were undetectable in IL-4-treated dermal fibroblasts, despite comparable levels of cell surface IL-4 receptor and phosphorylated Jak2 and STAT6. Our findings suggest that orbital connective tissues may represent a site of localized 15-hydroxyeicosatetraenoic acid generation resulting from cell type-specific 15-LOX-1 mRNA stabilization by IL-4. These results may have relevance to the pathogenesis of orbital Graves disease, an inflammatory autoimmune condition that gives way to extensive fibrosis associated with a Th2 response.