15-deoxy-Δ12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes
15-deoxy-Δ12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes
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DOI：
10.1074/jbc.m400492200
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发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Sobrino, F
中科院分区：
文献类型：
--
作者：
Alvarez-Maqueda, M;El Bekay, R;Sobrino, F
15-脱氧-三角洲(12，14)-前列腺素J(2)(15dPGJ(2))最近被认为是一种有效的抗炎药。然而，15dPGJ(2)在体内介导其治疗作用的机制尚不清楚。我们证明了微摩尔(2.5-10微米)浓度的15dPGJ(2)可诱导人淋巴细胞中一种抗炎酶--血红素加氧酶-1(HO-1)在mRNA和蛋白质水平上的表达。相反，曲格列酮和西格列酮这两种通过与过氧化物酶体增殖物激活受体(PPAR)-γ结合来模拟15dPGJ(2)的多种作用的噻唑烷二酮并不影响HO-1的表达，而15dPGJ(2)对这一过程的正向作用被其他环戊酮前列腺素(PG)所模拟，如15dPGJ(2)的前体PGD(2)、PGA(1)和PGA(2)不与PPAR-伽马相互作用。此外，15dPGJ(2)还能促进细胞内ROS的产生，提高黄嘌呤氧化酶的活性。N-乙酰半胱氨酸、TEMPO、Me2SO、1，10-邻菲咯啉或别嘌醇抑制细胞内ROS的产生，导致细胞内15dPGJ(2)依赖的HO-1表达减少。此外，还原型谷胱甘肽合成的抑制剂丁硫氨酸亚磺胺或Fe2+/Cu2+离子增强了15dPGJ(2)对HO-1表达的正向作用。另一方面，抑制磷脂酰肌醇3-激酶或p38丝裂原活化蛋白激酶，或阻断转录因子NF-kappaB的激活，可抑制15dPGJ(2)诱导的HO-1的表达。综上所述，目前的数据表明，15dPGJ(2)在药理浓度下的抗炎作用涉及诱导HO-1基因表达，其机制独立于PPAR-γ激活，并依赖于黄嘌呤/黄嘌呤氧化酶系统和/或Fenton反应产生的ROS。磷脂酰肌醇3-激酶和p38丝裂原活化蛋白激酶信号通路似乎也参与了15dPGJ(2)对HO-1表达的调控。
15-Deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) has been proposed recently as a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ(2) mediates its therapeutic effects in vivo are unclear. We demonstrate that 15dPGJ(2) at micromolar (2.5-10 muM) concentrations induces the expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, at both mRNA and protein levels in human lymphocytes. In contrast, troglitazone and ciglitazone, two thiazolidinediones that mimic several effects of 15dPGJ(2) through their binding to the peroxisome proliferator-activated receptor (PPAR)-gamma, did not affect HO-1 expression, and the positive effect of 15dPGJ(2) on this process was mimicked instead by other cyclopentenone prostaglandins ( PG), such as PGD(2) (the precursor of 15dPGJ(2)) and PGA(1) and PGA(2) which do not interact with PPAR-gamma. Also, 15dPGJ(2) enhanced the intracellular production of reactive oxygen species (ROS) and increased xanthine oxidase activity in vitro. Inhibition of intracellular ROS production by N-acetylcysteine, TEMPO, Me2SO, 1,10-phenanthroline, or allopurinol resulted in a decreased 15dPGJ(2)-dependent HO-1 expression in the cells. Furthermore, buthionine sulfoximine, an inhibitor of reduced glutathione synthesis, or Fe2+/Cu2+ ions enhanced the positive effect of 15dPGJ(2) on HO-1 expression. On the other hand, the inhibition of phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase, or the blockade of transcription factor NF-kappaB activation, hindered 15dPGJ(2)-elicited HO-1 expression. Collectively, the present data suggest that 15dPGJ(2) anti-inflammatory actions at pharmacological concentrations involve the induction of HO-1 gene expression through mechanisms independent of PPAR-gamma activation and dependent on ROS produced via the xanthine/xanthine oxidase system and/or through Fenton reactions. Both phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways also appear implicated in modulation of HO-1 expression by 15dPGJ(2).