磷脂酸在介导对TNF α和IL-1 β的炎症反应中的潜在作用。

Circulatory shock Pub Date : 1994-09-01
S Bursten, R Weeks, J West, T Le, T Wilson, D Porubek, J A Bianco, J W Singer, G C Rice
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引用次数: 0

摘要

肿瘤坏死因子α (TNF α)、白细胞介素1 β (IL-1 β)和内毒素(LPS)是有效的促炎介质,可在多种细胞类型中诱导多种多样的生物反应。然而,这些促炎介质在其生物学作用上也有显著的重叠和冗余。这表明,这些刺激诱导的第二信使信号转导系统存在显著的多样性,可以解释生物反应的多样性,以及显著的冗余性。在这里,我们展示了几种促炎刺激共同的第二信使之一可能是磷脂酸(PA)。细胞内PA可能具有细胞内信号功能,可通过TNF α、IL-1 β或LPS在P388单核细胞中快速诱导。这些PA种类根据键类型(即sn-1酯、醚、乙烯醚)、酰基链长度以及sn-1和sn-2位置的饱和程度而变化。虽然PA本身可能具有直接的第二信使活性,但许多诱导的PA物种转化为二酰基甘油物种(DG),它们在结构上与磷脂酰胆碱特异性磷脂酶C (PC-PLC)产生的DG不同。Lisofylline [(R) 1 - (5-hydroxyhexyl) 3, 7-dimethylxanthine;LSF]选择性抑制TNF α、IL-1 β或LPS诱导的P388细胞中特定种类PA的产生。TNF α诱导的鞘磷脂水解、plc介导的PC水解、DG激酶介导的PA形成或TNF α诱导的NF-kappa B活化和凋亡不受LSF的抑制。LSF在多种急性炎症动物模型中具有显著的保护作用,这可能是由于抑制了涉及PA的共享第二信使通路。
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Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta.

Tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and endotoxin (LPS) are potent pro-inflammatory mediators which induce multiple and diverse biological responses in a wide variety of cell types. However, these pro-inflammatory mediators also have significant overlap and redundancy in their biological effects. This suggests that there is significant diversity in second messenger signal transduction systems induced by these stimuli to explain the diversity in biological responses, as well as significant redundancy. Here we show that one such second messenger common to several proinflammatory stimuli may be phosphatidic acid (PA). Intracellular PA species, which may have intracellular signaling functions, are rapidly induced in P388 monocytic leukemia cells by TNF alpha, IL-1 beta, or LPS. These PA species vary according to the bond type (i.e., sn-1 ester vs. ether vs. vinyl ether), acyl chain length, and the degree of saturation in the sn-1 and sn-2 positions. Although PA itself may have direct second messenger activities, many of the PA species induced are converted to diacylglycerol species (DG), which are structurally distinct from the DGs generated by phosphatidylcholine-specific phospholipase C (PC-PLC). Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS. TNF alpha-induced sphingomyelin hydrolysis, PLC-mediated PC hydrolysis, and DG kinase-mediated PA formation or TNF alpha-induced NF-kappa B activation and apoptosis are not inhibited by LSF. LSF has a marked protective effect in a variety of acute inflammatory animal models that may be due to inhibition of this shared second messenger pathway involving PA.

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