Regulation of lung fibroblast activation by annexin A1
Regulation of lung fibroblast activation by annexin A1
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DOI：
10.1002/jcp.24156
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发表时间：
2013-02-01
影响因子：
5.6
通讯作者：
Yang, Yuan H.
中科院分区：
文献类型：
--
作者：
Jia, Yuan;Morand, Eric F.;Yang, Yuan H.
膜联蛋白A1（Annexin-A1，AnxA 1）是糖皮质激素诱导的蛋白质，在炎症细胞活化的调节中具有多种作用。AnxA 1对人类细胞生物学的贡献还不清楚。我们研究了AnxA 1及其受体甲酰基肽受体2（FPR 2）对人正常肺成纤维细胞（NLF）炎症反应调节的贡献。使用小干扰RNA（siRNA）沉默NLF中的组成性AnxA 1表达与肿瘤坏死因子（TNF）诱导的增殖和白细胞介素（IL）-6产生的中度但显著增加相关，同时伴有ERK和NF-κ B活性的降低。AnxA 1对ERK和NF-κ B活化的调节与对增殖的影响相关。使用特异性拮抗剂WRW 4阻断FPR 2模拟了AnxA 1沉默对TNF诱导的增殖、IL-6、ERK和NF-κ B活化的影响。AnxA 1沉默也损害了糖皮质激素对IL-6产生和糖皮质激素诱导的亮氨酸拉链（GILZ）表达的抑制作用，但阻断FPR 2未能模拟AnxA 1沉默的这些作用。这些数据表明，AnxA 1调节TNF诱导的肺成纤维细胞增殖和炎症反应，通过对ERK和NF-κ B途径，这取决于FPR 2的影响。AnxA 1还介导糖皮质激素和GILZ表达的作用，但这些作用似乎独立于FPR 2。这些发现表明，模拟AnxA 1的作用可能在慢性炎症性肺病中具有治疗潜力。J.细胞。《生理学》228：476484，2013年。(C)2012 Wiley Periodicals，Inc.
Annexin-A1 (AnxA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The contribution of AnxA1 to human cell biology is not well understood. We investigated the contribution of AnxA1 and its receptor, formyl-peptide receptor 2 (FPR2), to the regulation of inflammatory responses in human normal lung fibroblasts (NLF). Silencing constitutive AnxA1 expression in NLF using small interfering RNA (siRNA) was associated with moderate but significant increases in tumor necrosis factor (TNF)-induced proliferation and interleukin (IL)-6 production, accompanied by reduction of ERK and NF-kappa B activity. AnxA1 regulation of ERK and NF-kappa B activation was associated with effects on proliferation. Blocking FPR2 using the specific antagonist WRW4 mimicked the effects of AnxA1 silencing on TNF-induced proliferation, IL-6, ERK, and NF-kappa B activation. AnxA1 silencing also impaired inhibitory effects of glucocorticoid on IL-6 production and on the expression of glucocorticoid-induced leucine zipper (GILZ), but blocking FPR2 failed to mimic these effects of AnxA1 silencing. These data suggest that AnxA1 regulates TNF-induced proliferation and inflammatory responses in lung fibroblasts, via effects on the ERK and NF-kappa B pathways, which depend on FPR2. AnxA1 also mediates effects of glucocorticoids and GILZ expression, but these effects appear independent of FPR2. These findings suggest that mimicking AnxA1 actions might have therapeutic potential in chronic inflammatory lung diseases. J. Cell. Physiol. 228: 476484, 2013. (C) 2012 Wiley Periodicals, Inc.