Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively.
Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively.
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DOI：
10.4049/jimmunol.1002342
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发表时间：
2011-01-15
期刊：
影响因子：
--
通讯作者：
Jiang Q
中科院分区：
文献类型：
--
作者：
Jiang Z;Yin X;Jiang Q
5-脂氧合酶 (5-LOX) 催化反应产生的白三烯是炎症的关键调节因子。在离子载体刺激（A23187；1–2.5 μM）的人血中性粒细胞或分化的 HL-60 细胞中，维生素 E 形成差异性抑制的白三烯 B4 (LTB4)，对于 γ-生育酚、δ-生育酚 (δT) 和 γ-生育三烯酚的 IC50 为 5–20 μM，但对于α-生育酚。 13'-Carboxychromanol 是 δT 的长链代谢物，可抑制中性粒细胞和 HL-60 细胞生成的 LTB4，IC50 为 4–7 μM，并有效抑制人重组 5-LOX 活性，IC50 为 0.5–1 μM。相比之下，维生素 E 形式对人 5-LOX 活性没有影响，但会损害离子载体诱导的细胞内钙增加和钙内流，以及随后的信号传导，包括 ERK1/2 磷酸化和 5-LOX 从细胞质到细胞核的易位，这是 5-LOX 激活的关键事件。进一步研究表明，δT 抑制由离子载体、1-磷酸鞘氨醇和溶血磷脂酸触发的胞质 Ca2+ 增加和/或 LTB4 形成，但不通过 fMLP 或毒胡萝卜素触发，而无论刺激如何，13'-羧基苯并二氢吡喃醇都会减少细胞中 LTB4 的产生，这与其对 5-LOX 活性的强烈抑制作用一致。这些观察结果表明 δT 不太可能影响 fMLP 受体介导的信号传导或储存耗尽诱导的钙进入。相反，我们发现 δT 可以防止离子载体引起的细胞质膜破坏，这可能是它阻止钙流入的原因。维生素 E 形式和长链羧基苯并二氢吡喃醇的这些活性为维生素 E 形式在体内的不同抗炎作用提供了潜在的分子基础。
Leukotrienes generated by 5-lipoxygenase (5-LOX)–catalyzed reaction are key regulators of inflammation. In ionophore-stimulated (A23187; 1–2.5 μM) human blood neutrophils or differentiated HL-60 cells, vitamin E forms differentially inhibited leukotriene B4 (LTB4) with an IC50 of 5–20 μM for γ-tocopherol, δ-tocopherol (δT), and γ-tocotrienol, but a much higher IC50 for α-tocopherol. 13′-Carboxychromanol, a long-chain metabolite of δT, suppressed neutrophil- and HL-60 cell-generated LTB4 with an IC50 of 4–7 μM and potently inhibited human recombinant 5-LOX activity with an IC50 of 0.5–1 μM. In contrast, vitamin E forms had no effect on human 5-LOX activity but impaired ionophore-induced intracellular calcium increase and calcium influx as well as the subsequent signaling including ERK1/2 phosphorylation and 5-LOX translocation from cytosol to the nucleus, a key event for 5-LOX activation. Further investigation showed that δT suppressed cytosolic Ca2+ increase and/or LTB4 formation triggered by ionophores, sphingosine 1-phosphate, and lysophosphatidic acid but not by fMLP or thapsigargin, whereas 13′-carboxychromanol decreased cellular production of LTB4 regardless of different stimuli, consistent with its strong inhibition of the 5-LOX activity. These observations suggest that δT does not likely affect fMLP receptor-mediated signaling or store depletion-induced calcium entry. Instead, we found that δT prevented ionophore-caused cytoplasmic membrane disruption, which may account for its blocking of calcium influx. These activities by vitamin E forms and long-chain carboxychromanol provide potential molecular bases for the differential anti-inflammatory effects of vitamin E forms in vivo.
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影响因子：
5.5
作者：
Itagaki, K;Kannan, KB;Hauser, CJ
通讯作者：
Hauser, CJ
DOI：
10.1073/pnas.75.5.2458
发表时间：
1978-01-01
影响因子：
11.1
作者：
COLLINS, SJ;RUSCETTI, FW;GALLO, RC
通讯作者：
GALLO, RC
DOI：
10.1073/pnas.2133253100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Luo, M;Jones, SM;Brock, TG
通讯作者：
Brock, TG
影响因子：
6.5
作者：
Jiang, Qing;Freiser, Helene;Yin, Xinmin
通讯作者：
Yin, Xinmin
DOI：
10.1016/0005-2760(89)90047-7
发表时间：
1989-10-17
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CHAN, AC;TRAN, K;POWELL, WS
通讯作者：
POWELL, WS