Endothelial ICAM-1 Protein Induction Is Regulated by Cytosolic Phospholipase A2α via Both NF-κB and CREB Transcription Factors
Endothelial ICAM-1 Protein Induction Is Regulated by Cytosolic Phospholipase A2α via Both NF-κB and CREB Transcription Factors
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DOI：
10.4049/jimmunol.1000193
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发表时间：
2011-02-01
影响因子：
4.4
通讯作者：
Levy, Rachel
中科院分区：
文献类型：
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作者：
Hadad, Nurit;Tuval, Liron;Levy, Rachel
ICAM-1 的表达调节在炎症过程和免疫反应中发挥着重要作用。本研究旨在确定体内胞质磷脂酶 A(2)α (cPLA(2)α) 在炎症过程中 ICAM-1 过度表达中的参与情况，并阐明 cPLA(2)α 在导致内皮细胞中 ICAM-1 上调的信号事件中的特异性作用。在患有胶原诱导关节炎的小鼠发炎的爪子和高脂饮食小鼠的附睾周围脂肪组织中检测到 cPLA(2)α 和 ICAM-1 上调。静脉注射 2 mg/kg 针对 cPLA(2)α (AS) 的寡核苷酸反义寡核苷酸可减少 cPLA(2)α 上调，也可减少 ICAM-1 过表达，表明 cPLA(2)α 在炎症期间 ICAM-1 上调中发挥关键作用。表达ICAM-1的内皮ECV-304细胞和表达ICAM-1和VCAM-1的HUVEC与1μMA AS预孵育可防止cPLA(2)α和TNF-α诱导的粘附分子上调，并抑制它们对吞噬细胞样PLB细胞的粘附。虽然 AS 不抑制 NADPH 氧化酶 4-NADPH 氧化酶活性，但氧化酶活性的抑制减弱了 cPLA(2)α 的激活，表明 NADPH 氧化酶在 cPLA(2)α 的上游起作用。 AS 或二亚苯基碘鎓减弱 cPLA(2)α 的激活可阻止环加氧酶 2 的诱导和 PGE(2) 的产生，而 PGE(2) 是 ICAM-1 上调所必需的。 AS 抑制 cPLA(2)α 活性可抑制 p65 NF-kappa B 对 Ser(536) 和蛋白激酶 A 依赖性 CREB 的磷酸化。据我们所知，我们的结果首次表明 CREB 激活参与 ICAM-1 上调，并表明 NADPH 氧化酶激活的 cPLA(2)α 是未知激酶对 NF-κ B 进行顺序磷酸化以及 PGE(2) 介导的蛋白激酶 A 进行 CREB 激活所必需的。免疫学杂志，2011，186：1816-1827。
The regulated expression of ICAM-1 plays an important role in inflammatory processes and immune responses. The present study aimed to determine the in vivo involvement of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in ICAM-1 overexpression during inflammation and to elucidate the cPLA(2)alpha-specific role in signal events leading to ICAM-1 upregulation in endothelial cells. cPLA(2)alpha and ICAM-1 upregulation were detected in inflamed paws of mice with collagen-induced arthritis and in periepididymal adipose tissue of mice fed a high-fat diet. Intravenous injection of 2 mg/kg oligonucleotide antisense against cPLA(2)alpha (AS) that reduced cPLA(2)alpha upregulation also decreased ICAM-1 overexpression, suggesting a key role of cPLA(2)alpha in ICAM-1 upregulation during inflammation. Preincubation of endothelial ECV-304 cells that express ICAM-1 and of HUVEC that express ICAM-1 and VCAM-1 with 1 mu M AS prevented cPLA(2)alpha and the adhesion molecule upregulation induced by TNF-alpha and inhibited their adherence to phagocyte like-PLB cells. Whereas AS did not inhibit NADPH oxidase 4-NADPH oxidase activity, inhibition of oxidase activity attenuated cPLA(2)alpha activation, suggesting that NADPH oxidase acts upstream to cPLA(2)alpha. Attenuating cPLA(2)alpha activation by AS or diphenylene iodonium prevented the induction of cyclooxygenase-2 and the production of PGE(2) that were essential for ICAM-1 upregulation. Inhibition of cPLA(2)alpha activity by AS inhibited the phosphorylation of both p65 NF-kappa B on Ser(536) and protein kinase A-dependent CREB. To our knowledge, our results are the first to show that CREB activation is involved in ICAM-1 upregulation and suggest that cPLA(2)alpha activated by NADPH oxidase is required for sequential phosphorylation of NF-kappa B by an undefined kinase and CREB activation by PGE(2)-mediated protein kinase A. The Journal of Immunology, 2011, 186: 1816-1827.