Induction of heme oxygenase-1 expression in murine macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-Δ12,14-prostaglandin J2
Induction of heme oxygenase-1 expression in murine macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-Δ12,14-prostaglandin J2
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DOI：
10.1074/jbc.m300498200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Chau, LY
中科院分区：
文献类型：
--
作者：
Lee, TS;Tsai, HL;Chau, LY
15-脱氧-δ（12，14）-前列腺素J（2）（15 d-PGJ（2））是一种环戊烯酮前列腺素，在微摩尔浓度（> 2 μ M）下通过直接抑制核因子（NF）-κ B活化而显示出有效的抗炎作用。在此，我们发现，在亚微摩尔浓度（0.1-0.5 μ M）下，15 d-PGJ（2）在长时间孵育（> 12小时）的条件下仍能抑制脂多糖（LPS）激活的小鼠J774巨噬细胞中肿瘤坏死因子-α（TNF-α）和一氧化氮（NO）的产生。蛋白质印迹分析显示，细胞保护酶血红素加氧酶-1（HO-1）的表达被诱导，并且与15 d-PGJ的抗炎作用一致（2）。抑制HO-1活性或清除血红素降解产生的副产物一氧化碳（CO）可显著减弱15 d-PGJ的抑制活性（2）。此外，通过NF-κ B（IkappaB）降解和p50核转位抑制蛋白评估的LPS诱导的NF-κ B活化在用低浓度15 d-PGJ长时间处理的细胞中减少（2）。用蛋白质合成抑制剂放线菌酮或特异性p38 MAP激酶抑制剂SB 203580处理细胞，可阻断HO-1的诱导和LPS诱导的15 d-PGJ介导的IkappaB降解的抑制（2）。同样，HO抑制剂和CO清除剂可有效消除15 d-PGJ（2）对LPS诱导的NF-κ B活化的抑制作用。CO的功能作用进一步证明了使用一氧化碳释放分子，三羰基二氯钌（II）二聚体，显着抑制LPS诱导的核转位p50的共聚焦免疫荧光评估。总的来说，这些数据表明，即使在亚微摩尔浓度下，15 d-PGJ（2）也可以通过涉及HO/CO作用的机制在巨噬细胞中发挥抗炎作用。
15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a cyclopentenone prostaglandin, displays a potent anti-inflammatory effect at micromolar concentrations (> 2 muM) through direct inhibition of nuclear factor (NF)-kappaB activation. Here we show that at submicromolar concentrations (0.1-0.5 muM) 15d-PGJ(2) retains the ability to suppress the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide ( NO) in lipopolysaccharide (LPS)-activated murine J774 macrophages under the conditions of a prolonged incubation (> 12 h). Western blot analysis revealed that the expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), was induced and coincident with the anti-inflammatory action of 15d-PGJ(2). Inhibition of HO-1 activity or scavenging carbon monoxide (CO), a byproduct derived from heme degradation, significantly attenuated the suppressive activity of 15d-PGJ(2). Furthermore, LPS-induced NF-kappaB activation assessed by the inhibitory protein of NF-kappaB (IkappaB) degradation and p50 nuclear translocation was diminished in cells subjected to prolonged treatment with the low concentration of 15d-PGJ(2). Treatment of cells with the protein synthesis inhibitor, cycloheximide, or the specific p38 MAP kinase inhibitor, SB203580, blocked the induction of HO-1 and suppression of LPS-induced IkappaB degradation mediated by 15d-PGJ(2). Likewise, HO inhibitor and CO scavenger were effective in abolishing the inhibitory effects of 15d-PGJ(2) on NF-kappaB activation induced by LPS. The functional role of CO was further demonstrated by the use of a CO releasing molecule, tricarbonyldichlororuthenium(II) dimer, which significantly suppressed LPS-induced nuclear translocation of p50 as assessed by confocal immunofluorescence. Collectively, these data suggest that even at submicromolar concentrations 15d-PGJ(2) can exert an anti-inflammatory effect in macrophages through a mechanism that involves the action of HO/CO.