Ray Denise M, Akbiyik Filiz, Phipps Richard P
Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
J Immunol. 2006 Oct 15;177(8):5068-76. doi: 10.4049/jimmunol.177.8.5068.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARgamma ligands, including the endogenous ligand 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARgamma for apoptosis induction is unknown. In this study, we used a PPARgamma dominant-negative approach and a small molecule irreversible PPARgamma antagonist and found that these inhibitors prevented PPARgamma activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARgamma agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARgamma but did not kill B lymphocytes, further supporting a non-PPARgamma-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARgamma may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARgamma agonists. Furthermore, these new findings support continued investigation into the use of PPARgamma agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种对脂肪生成很重要的转录因子，最近已被证明是一个抗癌靶点。PPARγ配体，包括内源性配体15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）以及如罗格列酮和曲格列酮等合成配体，均可诱导正常和恶性人B淋巴细胞凋亡，但PPARγ对凋亡诱导的依赖性尚不清楚。在本研究中，我们采用PPARγ显性负性方法和一种小分子不可逆PPARγ拮抗剂，发现这些抑制剂可阻止PPARγ激活，但不能阻止15d-PGJ2或罗格列酮诱导的B细胞凋亡。此外，一种作为15d-PGJ2结构类似物且缺乏15d-PGJ2环戊烯酮环亲电碳的PPARγ激动剂，可激活PPARγ但不杀伤B淋巴细胞，进一步支持了非PPARγ介导的机制。为进一步研究凋亡机制，研究了15d-PGJ2和罗格列酮对活性氧的影响。15d-PGJ2而非罗格列酮可有效诱导B淋巴细胞中的活性氧，提示15d-PGJ2结构的反应性在凋亡机制中起作用。此外，15d-PGJ2几乎可使细胞内谷胱甘肽完全耗尽。而且，用抗氧化剂谷胱甘肽乙酯孵育可阻止15d-PGJ2诱导的凋亡，但不能阻止罗格列酮诱导的凋亡。这些发现表明，PPARγ的表达可能无法预测正常或恶性B系细胞对PPARγ激动剂是否敏感。此外，这些新发现支持继续研究将PPARγ激动剂用作减弱正常B细胞反应的药物以及抗B细胞淋巴瘤药物。
