Faculty of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai-Iino, Iwaki, Fukushima 970-8551, Japan.
Eur J Pharmacol. 2013 Aug 15;714(1-3):142-7. doi: 10.1016/j.ejphar.2013.05.050. Epub 2013 Jun 19.
Platelet-activating factor (PAF), a potent proinflammatory mediator, is involved in many inflammatory diseases. We recently reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence inhibit PAF-induced inflammation by directly binding to PAF. In this study, we investigated the effect of two synthetic biotinylated peptides, both of which have a sequence similar to Tyr-Lys-Asp-Gly-an endothelin-3 (ET-3)-related biotinylated pentapeptide (Tyr-Lys-Asp-Lys-Glu, BPET3) and a scavenger receptor CD36-related biotinylated tetrapeptide (Tyr-Lys-Gly-Lys, BPCD36)-on PAF-induced inflammation by using a rat model of hind paw oedema. BPET3 markedly inhibited PAF-induced oedema in a dose-dependent manner, and the dose that caused 50% inhibition was estimated to be approximately 2.64 nmol/paw. The inhibitory effect of BPCD36 on PAF-induced paw oedema was less than that of BPET3, while a synthetic biotinylated pentapeptide (Lys-Lys-Tyr-Asp-Glu) shuffling amino acid sequence of BPET3, an ET-1-related synthetic biotinylated pentapeptide (Leu-Met-Asp-Lys-Glu), or an ET-2-related synthetic biotinylated pentapeptide (Trp-Leu-Asp-Lys-Glu) did not inhibit PAF-induced paw oedema. Furthermore, intrinsic tryptophan fluorescence studies demonstrated that ET-3 specifically interacted with both PAF and its metabolite/precursor lyso-PAF. These results provide evidence that the Tyr-Lys-Asp region in both ET-3 and BPET3 is essential for marked inhibition of the peptide on PAF-induced inflammation, and strongly suggest that BPET3 may be useful as a novel anti-inflammatory drug targeting PAF.
血小板激活因子（PAF）是一种有效的促炎介质，参与许多炎症性疾病。我们最近报道，具有 Tyr-Lys-Asp-Gly 序列的合成生物素化肽通过直接与 PAF 结合来抑制 PAF 诱导的炎症。在这项研究中，我们使用大鼠后爪水肿模型研究了两种合成生物素化肽对 PAF 诱导的炎症的影响，这两种肽都具有与 Tyr-Lys-Asp-Gly 相似的序列，一种是内皮素-3（ET-3）相关的生物素化五肽（Tyr-Lys-Asp-Lys-Glu，BPET3），另一种是清道夫受体 CD36 相关的生物素化四肽（Tyr-Lys-Gly-Lys，BPCD36）。BPET3 可显著抑制 PAF 诱导的水肿，且抑制 50%水肿所需的剂量约为 2.64 nmol/爪。BPCD36 对 PAF 诱导的爪水肿的抑制作用弱于 BPET3，而一种合成生物素化五肽（Lys-Lys-Tyr-Asp-Glu）打乱了 BPET3 的氨基酸序列，一种 ET-1 相关的合成生物素化五肽（Leu-Met-Asp-Lys-Glu）或一种 ET-2 相关的合成生物素化五肽（Trp-Leu-Asp-Lys-Glu）则不能抑制 PAF 诱导的爪水肿。此外，内源性色氨酸荧光研究表明，ET-3 特异性地与 PAF 及其代谢物/前体溶血 PAF 相互作用。这些结果提供了证据，表明 ET-3 和 BPET3 中的 Tyr-Lys-Asp 区域对于肽对 PAF 诱导的炎症的显著抑制是必不可少的，并强烈表明 BPET3 可能作为一种新型靶向 PAF 的抗炎药物是有用的。
