Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain.
Biochem Pharmacol. 2010 Jun 15;79(12):1797-804. doi: 10.1016/j.bcp.2010.02.008. Epub 2010 Feb 21.
Bovine glycomacropeptide (GMP) is an immunologically active milk peptide that is a part of the normal human diet. GMP has therapeutic value in preclinical models of intestinal inflammation, and its mechanism may be related to effects on lymphocytes. This study focuses on the actions of GMP on rat splenocytes in vitro and in vivo. Bovine serum albumin and lactoferrin were used for comparative purposes. GMP (0.01-0.1mgmL(-1)) enhanced Concanavalin A (ConA) evoked but not basal splenocyte proliferation. At 1mgmL(-1) GMP lost this effect but augmented basal TNF-alpha secretion and also iNOS and COX2 expression. IFN-gamma, IL-2 and IL-17 were not affected by GMP in quiescent splenocytes, but IL-10 was augmented at all concentrations tested. On the other hand, GMP produced a marked inhibitory effect (70%) on IFN-gamma secretion and to a lower extent (50%) also on TNF-alpha. GMP was shown to block STAT4 but not IkappaB-alpha phosphorylation. The Treg marker Foxp3 was markedly upregulated by GMP. Bovine serum albumin had some effects on splenocyte function which were of lower magnitude and not entirely coincidental, while lactoferrin had a strong antiproliferative effect, as expected, indicating a specific effect of GMP. When administered for 3 days to normal Wistar rats, GMP reproduced the Foxp3 induction effect observed previously in vitro. This was observed in splenocytes but not in thymocytes, and only when administered by the oral rather than the intraperitoneal route. Thus our results support the hypothesis that GMP may limit intestinal inflammation acting at least in part on lymphocytes.
牛糖巨肽（GMP）是一种具有免疫活性的乳肽，是正常人类饮食的一部分。GMP 在肠道炎症的临床前模型中具有治疗价值，其机制可能与对淋巴细胞的影响有关。本研究重点研究 GMP 对体外和体内大鼠脾细胞的作用。牛血清白蛋白和乳铁蛋白被用作比较目的。GMP（0.01-0.1mgmL（-1））增强了刀豆蛋白 A（ConA）诱发的但不是基础的脾细胞增殖。在 1mgmL（-1）GMP 失去了这种作用，但增强了基础 TNF-α分泌，以及 iNOS 和 COX2 的表达。IFN-γ、IL-2 和 IL-17 在静止的脾细胞中不受 GMP 影响，但在所有测试浓度下均增加了 IL-10。另一方面，GMP 对 IFN-γ分泌产生了显著的抑制作用（70%），对 TNF-α的抑制作用较低（50%）。GMP 被证明可以阻断 STAT4，但不能阻断 IkappaB-α磷酸化。Treg 标记物 Foxp3 被 GMP 明显上调。牛血清白蛋白对脾细胞功能有一些影响，但影响较小，并不完全一致，而乳铁蛋白具有很强的抗增殖作用，这是预期的，表明 GMP 具有特异性作用。当连续 3 天给予正常 Wistar 大鼠时，GMP 再现了先前在体外观察到的 Foxp3 诱导作用。这在脾细胞中观察到，但在胸腺细胞中没有观察到，并且仅在口服而不是腹腔内给药时观察到。因此，我们的结果支持这样一种假设，即 GMP 可能通过至少部分作用于淋巴细胞来限制肠道炎症。
