Lysophosphatidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: Potential anti-inflammatory signaling pathways
Lysophosphatidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: Potential anti-inflammatory signaling pathways
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DOI：
10.2119/2007-00106.fan
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发表时间：
2008-07-01
影响因子：
5.7
通讯作者：
Cook, James A.
中科院分区：
文献类型：
--
作者：
Fan, Hongkuan;Zingarelli, Basilia;Cook, James A.
先前的研究表明，异源三聚体鸟嘌呤核苷酸结合调节（Gi）蛋白缺陷小鼠表现出增强的炎症反应脂多糖（LPS）。这些结果表明，Gi蛋白激动剂可以抑制LPS诱导的炎症基因表达，溶血磷脂酸（LPA）激活G蛋白偶联受体，导致Gi蛋白激活。我们假设LPA通过激活Gi偶联的抗炎信号通路来抑制LPS诱导的炎症反应。我们在CD-1小鼠体内和体外检测了LPA对LIPS反应的抗炎作用。LPA（10 mg/kg）静脉注射后腹腔注射LIPS（75 mg/kg），利达显著提高小鼠内毒素血症存活率（P < 0.05）。与注射溶剂相比，注射LPA可降低LPS诱导的血浆TNF-α的产生（69 ± 6%，P < 0.05）和肺中髓过氧化物酶（MPO）的活性（33 ± 9%，P < 0.05），而LPS诱导的血浆IL-6不受LPA的影响。腹腔巨噬细胞的体外研究结果与体内研究结果一致。利达（1和10 μ M）显著抑制LPS诱导的TNF α产生（分别为61 +/- 9%和72 +/-9%，P < 0.05），但不抑制IL-6。我们进一步证明LPA的抗炎作用可被ERK 1/2和磷酸酶抑制剂逆转，表明ERK 1/2途径和丝氨酸/苏氨酸磷酸酶参与。抑制磷脂酰肌醇3（P13）激酶信号通路也部分逆转了利达的抗炎反应，但LPA并不改变NF κ B B和过氧化物酶体增殖物激活受体γ（PPAR γ）的活化。这些研究表明，LPA具有显著的抗炎活性，涉及ERK 1/2、丝氨酸/苏氨酸磷酸酶和P13激酶信号通路的激活。
Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression, Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation. We hypothesized that LPA will inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways. We examined the anti-inflammatory effect of LPA on LIPS responses both in vivo and in vitro in CD-I mice. The mice were injected intravenously with LPA (10 mg/kg) followed by intraperitoneal injection of LIPS (75 mg/kg for survival and 25 mg/kg for other studies), LIDA significantly increased the mice survival to endotoxemia (P < 0.05). LPA injection reduced LPS-induced plasma TNF-alpha production (69 +/- 6%, P < 0.05) and myeloperoxidase (MPO) activly in lung (33 +/- 9%, P < 0.05) as compared to vehicle injection, LPS-induced plasma IL-6 was unchanged by LPA. In vitro studies with peritoneal macrophages paralleled results from in vivo studies. LIDA (1 and 10 mu M) significantly inhibited LPS-induced TNF alpha production (61 +/- 9% and 72 +/- 9%, respectively, P < 0.05) but not IL-6. We further demonstrated that the anti-inflammatory effect of LPA was reversed by ERK 1/2 and phosphatase inhibitors, suggesting that ERK 1/2 pathway and serine/threonine phosphatases are involved. Inhibition of phosphatidylinositol 3 (P13) kinase signaling pathways also partially reversed the LIDA anti-inflammatory response, However, LPA did not alter NF kappa B and peroxisome proliferator-activated receptor gamma (PPAR gamma) activation. Inhibitors of PPAR gamma did not alter LPA-induced inhibition of LIPS signaling, These studies demonstrate that LPA has significant anti-inflammatory activities involving activation of ERK 1/2, serine/threonine phosphatases, and P13 kinase signaling pathways.