Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1β production
Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1β production
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DOI：
10.1046/j.1471-4159.1999.0720565.x
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发表时间：
1999-02-01
影响因子：
4.7
通讯作者：
Kraig, RP
中科院分区：
文献类型：
--
作者：
Caggiano, AO;Kraig, RP
前列腺素（PGs）是正常和病理条件下脑功能的有效调节剂。前列腺素的不同作用是由于这些前列腺素类的特异性受体亚型的不同作用。最近的研究表明，PGE（2），虽然通常被认为是一种促炎分子，减少小胶质细胞的激活，从而对这些细胞有抑制作用。为了进一步了解PGE（2）影响小胶质细胞活化的机制，我们研究了PGE受体亚型，即，EP 1、EP 2、EP 3和EP 4在培养的大鼠小胶质细胞中的表达和功能。RT-PCR结果显示，EP 1和EP 2受体亚型的存在，但没有EP 3和EP 4受体亚型。测序证实了他们的身份与以前公布的受体亚型。PGE（2）和EP 1激动剂17-phenyl trinor PGE（2），而不是EP 3激动剂硫前列酮，引起小胶质细胞内[Ca 2 +]的可逆增加，通过fura-2测量。PGE（2）和EP 2/EP 4特异性激动剂11-脱氧-PGE（1）和19-羟基-PGE（2）诱导环腺苷酸（cAMP）的剂量依赖性产生，但EP 4选择性激动剂1-羟基-PGE（1）不诱导。在存在或不存在受体亚型激动剂的情况下，还测量了脂多糖暴露后白细胞介素（IL）-1 β的产生，这是活化的小胶质细胞的标志物。PGE（2）和EP 2激动剂减少IL-1 β的产生。IL-1 β的产生不受EP 1、EP 3和EP 4激动剂的影响。腺苷酸环化酶激活剂毛喉素和cAMP类似物二丁酰cAMP也减少IL-1 β的产生。因此，PGE（2）对小胶质细胞的抑制作用是由EP 2受体亚型介导的，这种作用的信号传导机制可能是通过cAMP。这些结果表明，PGE（2）对小胶质细胞的作用是受体亚型特异性的。此外，它们表明，特异性和选择性操纵PGs对小胶质细胞的作用，从而影响脑功能是可能的。
Prostaglandins (PGs) are potent modulators of brain function under normal and pathological conditions. The diverse effects of PGs are due to the various actions of specific receptor subtypes for these prostanoids. Recent work has shown that PGE(2), while generally considered a proinflammatory molecule, reduces microglial activation and thus has an antiinflammatory effect on these cells. To gain further insight to the mechanisms by which PGE(2), influences the activation of microglia, we investigated PGE receptor subtype, i,e., EP1, EP2, EP3, and EP4, expression and function in cultured rat microglia. RT-PCR showed the presence of the EP1 and EP2 but not EP3 and EP4 receptor subtypes. Sequencing confirmed their identity with previously published receptor subtypes. PGE(2) and the EP1 agonist 17-phenyl trinor PGE(2) but not the EP3 agonist sulprostone elicited reversible intracellular [Ca2+] increases in microglia as measured by fura-2. PGE(2) and the EP2/EP4-specific agonists 11-deoxy-PGE(1) and 19-hydroxy-PGE(2), but not the EP4-selective agonist l-hydroxy-PGE(1) induced dose-dependent production of cyclic AMP (cAMP). Interleukin (IL)-1 beta production, a marker of activated microglia, was also measured following lipopolysaccharide exposure in the presence or absence of the receptor subtype agonists. PGE(2) and the EP2 agonists reduced IL-1 beta production. IL-l beta production was unchanged by EP1, EP3, and EP4 agonists. The adenylyl cyclase activator forskolin and the cAMP analogue dibutyryl cAMP also reduced IL-1 beta production. Thus, the inhibitory effects of PGE(2) on microglia are mediated by the EP2 receptor subtype, and the signaling mechanism of this effect is likely via cAMP. These results show that the effects of PGE(2) on microglia are receptor subtype-specific, Furthermore, they suggest that specific and selective manipulation of the effects of PGs on microglia and, as a result, brain function may be possible.