AMP-activated protein kinase mediates T cell activation-induced expression of FasL and COX-2 via protein kinase C theta-dependent pathway in human Jurkat T leukemia cells
AMP-activated protein kinase mediates T cell activation-induced expression of FasL and COX-2 via protein kinase C theta-dependent pathway in human Jurkat T leukemia cells
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DOI：
10.1016/j.cellsig.2012.01.015
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发表时间：
2012-06-01
影响因子：
4.8
通讯作者：
Kang, Insug
中科院分区：
文献类型：
--
作者：
Lee, Jung Yeon;Choi, A-Young;Kang, Insug
AMP活化蛋白激酶（AMPK）是一种重要的能量稳态调节因子，在T细胞活化过程中被激活。通过T细胞受体（TCR）接合或其药理学模拟物PMA加离子霉素（PMA/Io）的T细胞活化诱导免疫调节性FasL和环氧合酶-2（考克斯-2）表达。本研究探讨AMPK在PMA/Io诱导Jurkat T细胞FasL和考克斯-2表达中的作用及其机制。通过药物、化合物C或AMPK α 1 siRNA抑制AMPK抑制PMA/IO激活的Jurkat细胞中FasL和考克斯-2 mRNA和蛋白质的表达。它还减少了用PMA/Io或单克隆抗CD 3+抗CD 28激活的Jurkat细胞和外周血淋巴细胞中FasL蛋白和前列腺素E2（考克斯-2的主要产物）的分泌。AMPK的抑制可阻断活化Jurkat细胞中FasL和考克斯-2的启动子活性。由于蛋白激酶C θ（PKC θ）是TCR信号传导的中心分子，我们研究了活化T细胞中AMPK和PKC θ之间任何可能的串扰。特别重要的是，我们发现AMPK的抑制阻断了PKC θ的磷酸化和激活，这表明AMPK是PKC θ的上游激酶。此外，我们发现AMPK直接与PKC θ和磷酸化的PKC θ的Thr 538在PMA/IO刺激的Jurkat细胞。我们还发现，在活化的Jurkat细胞中，通过rottlerin或显性负性PKC θ抑制PKC θ可降低AMPK介导的NF-AT和AP-1的转录活化。总之，这些结果表明，AMPK通过PKC θ和NF-AT和AP-1途径调节活化Jurkat细胞中FasL和考克斯-2的表达。(c)2012 Elsevier Inc. All rights reserved.
AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, is known to be activated during T cell activation. T cell activation by T cell receptor (TCR) engagement or its pharmacological mimics, PMA plus ionomycin (PMA/Io), induces immunomodulatory FasL and cyclooxygenase-2 (COX-2) expression. In this study, we examined the role and mechanisms of AMPK in PMA/Io-induced expression of FasL and COX-2 in Jurkat T human leukemic cells. Inhibition of AMPK by a pharmacological agent, compound C, or AMPK alpha 1 siRNA suppressed expression of FasL and COX-2 mRNAs and proteins in PMA/Io-activated Jurkat cells. It also reduced secretion of FasL protein and prostaglandin E2, a main product of COX-2, in Jurkat cells and peripheral blood lymphocytes activated with PMA/Io or monoclonal anti-CD3 plus anti-CD28. Consistently, inhibition of AMPK blocked promoter activities of FasL and COX-2 in activated Jurkat cells. As protein kinase C theta (PKC theta) is a central molecule for TCR signaling, we examined any possible cross-talk between AMPK and PKC theta in activated T cells. Of particular importance, we found that inhibition of AMPK blocked phosphorylation and activation of PKC theta, suggesting that AMPK is an upstream kinase of PKC theta. Moreover, we showed that AMPK was directly associated with PKC theta and phosphorylated Thr538 of PKC theta in PMA/Io-stimulated Jurkat cells. We also showed that inhibition of PKC theta by rottlerin or dominant negative PKC theta reduced AMPK-mediated transcriptional activation of NF-AT and AP-1 in activated Jurkat cells. Taken together, these results suggest that AMPK regulates expression of FasL and COX-2 via the PKC theta and NF-AT and AP-1 pathways in activated Jurkat cells. (c) 2012 Elsevier Inc. All rights reserved.