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

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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.