Regulatory mechanism to avoid or induce apoptosis in lymphocytes by AMP-activated protein kinase

炎性病变中T淋巴细胞的动态变化受不同应激状态下细胞增殖和凋亡的调节。为了阐明在应激状态下避免或诱导T淋巴细胞凋亡的分子机制，研究了不同应激条件下小鼠胸腺细胞和咬肌中AMPK的作用。AMPK是一种被AMP激活的酶，作为代谢主开关，能够介导细胞对各种应激的适应，是由催化α和调节(β，γ)亚基组成的异三聚体复合体。每个亚基有2-3个亚型。研究表明，不同组织中AMPK亚基及其异构体的细胞含量不同，提示AMPK在组织中的功能和活性调节不同。饥饿应激可引起胸腺和咬肌萎缩，并伴有细胞凋亡。饥饿应激诱导胸腺和咬肌细胞凋亡的主要亚型，部分是由应激激素糖皮质激素诱导的。AICAR激活AMPK抑制包括糖皮质激素在内的各种刺激诱导的胸腺细胞凋亡。AICAR通过激活蛋白激酶C而增强对细胞凋亡的抑制作用，提示AMPK和PKC信号通路之间存在相互作用。活化诱导的细胞死亡(AICD)在T细胞的内稳态中起重要作用，Fas配体(FasL)的表达参与了AICD的发生。蛋白酶体抑制剂通过阻断ERK激活和激活AMK抑制TCR刺激后FasL的表达。这些结果表明，AMPK在不同的应激状态下具有诱导或避免细胞凋亡的重要作用。

T lymphocyte dynamics in inflammatory lesions are regulated by proliferation and apoptosis of the cells under various stresses. To elucidate the molecular mechanisms to avoid or induce apoptosis under stresses in T lymphocyte, the role of AMP-activated protein kinase (AMPK) was investigated in murine thymocytes and masseter muscle under various stress conditions. AMPK is known to be an enzyme activated by AMP and acting as a metabolic master switch capable of mediating the cellular adaptation to various stresses, and is a heterotrimeric complex consisting of a catalytic α and regulatory (β,γ) subunits. Each subunit has 2-3 isoforms. The present study showed that the cellular contents of the subunits and their isoform were different among tissues, suggesting different functions and regulation of AMPK activity in tissues. Starvation stress induced atrophy of thymus and masseter muscle associated with apoptosis. The main isoforms in thymus and masseter muscle induced by starvation stress which induced apoptosis in part by a stress hormone glucocorticoid.Activation of AMPK by AICAR inhibited thymocyte apoptosis induced by various stimuli including glucocorticoid. Inhibition of apoptosis by AICAR was enhanced by activating protein kinase C, suggesting the interaction between AMPK and PKC pathways. Activation-induced cell death (AICD) plays a critical role in the homeostasis of T lymphocytes and Fas ligand (FasL) expression was involved in AICD. Expression of FasL following TCR stimulation was inhibited by proteasome inhibitors through blocking ERK activation as well as by activating AMPK.These results suggest that AMPK has an important role to induce or avoid apoptosis under various stresses.