Apigenin, a dietary flavonoid, sensitizes human T cells for activation-induced cell death by inhibiting PKB/Akt and NF-κB activation pathway

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• 作者：Luting Xu ; Li Zhang ; Anne M. Bertucci ; Richard M. Pope ; Syamal K. Datta
• 关键词：Apoptosis ; T cells ; Human ; Signal transduction ; Autoimmunity
• 刊名：Immunology Letters
• 出版年：2008
• 出版时间：16 November 2008
• 年：2008
• 卷：121
• 期：1
• 页码：74-83
• 全文大小：1115 K

文摘

Resistance of T cells to activation-induced cell death (AICD) is associated with autoimmunity and lymphoproliferation. We found that apigenin (4′,5,7-trihydroxyflavone), a non-mutagenic dietary flavonoid, augmented both extrinsic and intrinsic pathways of apoptosis in recurrently activated, but not in primarily stimulated, human blood CD4+ T cells. Apigenin potentiated AICD by inhibiting NF-κB activation and suppressing NF-κB-regulated anti-apoptotic molecules, cFLIP, Bcl-x_L, Mcl-1, XIAP and IAP, but not Bcl-2. Apigenin suppressed NF-κB translocation to nucleus and inhibited IκBα phosphorylation and degradation in response to TCR stimulation in reactivated peripheral blood CD4 T cells, as well as in leukemic Jurkat T cell lines. Among the pathways that lead to NF-κB activation upon TCR stimulation, apigenin selectively inhibited PI3K-PKB/Akt, but not PKC-θ activation in the human T cells, and synergized with a PI3K inhibitor to markedly augment AICD. Apigenin also suppressed expression of anti-apoptotic cyclooxygenase 2 (COX-2) protein in activated human T cells, but it did not affect activation of Erk MAPKinase. Thus, in chronically activated human T cells, relatively non-toxic apigenin can suppress anti-apoptotic pathways involving NF-κB activation, and especially cFLIP and COX-2 expression that are important for functioning and maintenance of immune cells in inflammation, autoimmunity and lymphoproliferation.