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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• 作者：Jung Yeon Lee^a ; ¹ ; A-Young Choi^a ; ¹ ; Young Taek Oh^a ; Wonchae Choe^a ; Eui-Ju Yeo^b ; Joohun Ha^a ; Insug Kang^a ; ^{iskang@khu.ac.kr}
• 关键词：AMPK ; AMP-activated protein kinase ; PKC ; protein kinase C ; TCR ; T cell receptor ; Fas ligand ; FasL ; COX-2 ; cyclooxygenase-2 ; NF-AT ; nuclear factor of activated T cells ; AP-1 ; activator protein-1 (AP-1) ; NF-魏B ; nuclear factor-kappaB ; PMA ; phorbol 12-myrist
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1195-1207
• 文件大小：1607 K

摘要

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伪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胃) is a central molecule for TCR signaling, we examined any possible cross-talk between AMPK and PKC胃 in activated T cells. Of particular importance, we found that inhibition of AMPK blocked phosphorylation and activation of PKC胃, suggesting that AMPK is an upstream kinase of PKC胃. Moreover, we showed that AMPK was directly associated with PKC胃 and phosphorylated Thr538 of PKC胃 in PMA/Io-stimulated Jurkat cells. We also showed that inhibition of PKC胃 by rottlerin or dominant negative PKC胃 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胃 and NF-AT and AP-1 pathways in activated Jurkat cells.