Warren Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI 02905-2499, USA.
Neuroimmunomodulation. 2010;17(6):405-10. doi: 10.1159/000288265. Epub 2010 May 28.
The cytokines interleukin (IL)-1beta and IL-6 are modulators of the neuroimmune axis and have been implicated in neuronal cell death cascades after ischemia or infection. Previous work has shown that some cross-species conservation exists between human and rodent blood-brain barrier (BBB) transport systems. To further assess cross-species conservation of cytokine transport across the BBB, the current studies investigated permeability and inhibition of ovine IL-1beta and IL-6 in the mouse.
IL-1beta or IL-6 was radioactively labeled with (131)I and injected into the jugular vein at time zero. A subset of mice received 1 or 3 microg/mouse of an unlabeled ovine or murine cytokine (IL-1beta or IL-6) to assess self- and/or cross-inhibition of transport. Permeability was assessed using multiple-regression analysis.
There was a significant linear relationship for both ovine (131)I-IL-1beta and (131)I-IL-6 between brain/serum ratios and exposure time, indicating BBB permeability. Inclusion of 3 microg/mouse unlabeled ovine IL-1beta or IL-6 significantly reduced the transport of ovine (131)I-IL-1beta or (131)I-IL-6, respectively, across the BBB. Transport of both ovine (131)I-IL-1beta and (131)I-IL-6 was significantly inhibited by 1 microg/mouse of murine IL-1beta or IL-6, respectively. In contrast, 1 microg/mouse of unlabeled ovine IL-1beta or IL-6 did not inhibit the transport of murine (131)I-IL-1beta or (131)I-IL-6.
Ovine IL-1beta and IL-6 cross the mouse BBB by saturable transport. Inhibition of transport by murine homologs indicates that both species use the same transport mechanisms. Conversely, an inability of ovine cytokines to significantly inhibit the transport of murine cytokines indicates that mouse BBB has a lower affinity for ovine than murine cytokines. Knowledge of species-conserved BBB transport mechanisms may facilitate the development of novel animal models of central nervous system pathogenesis.
细胞因子白细胞介素（IL）-1β和 IL-6 是神经免疫轴的调节剂，并且与缺血或感染后的神经元细胞死亡级联反应有关。先前的工作表明，人类和啮齿动物血脑屏障（BBB）转运系统之间存在一些种属间的保守性。为了进一步评估细胞因子通过 BBB 的种属间保守性，本研究检测了绵羊细胞因子（IL-1β和 IL-6）在小鼠中的通透性和抑制作用。
用放射性碘标记（131）I 标记 IL-1β 或 IL-6，并在零时刻经颈静脉注射。一部分小鼠接受 1 或 3μg/只未标记的绵羊或鼠细胞因子（IL-1β 或 IL-6），以评估自身和/或交叉转运的抑制作用。采用多元回归分析评估通透性。
绵羊（131）I-IL-1β 和（131）I-IL-6 的脑/血清比与暴露时间之间均存在显著的线性关系，表明 BBB 通透性。加入 3μg/只未标记的绵羊 IL-1β 或 IL-6 分别显著降低了绵羊（131）I-IL-1β 或（131）I-IL-6 的 BBB 转运。1μg/只鼠 IL-1β 或 IL-6 分别显著抑制了绵羊（131）I-IL-1β 和（131）I-IL-6 的转运。相反，1μg/只未标记的绵羊 IL-1β 或 IL-6 不能抑制鼠（131）I-IL-1β 或（131）I-IL-6 的转运。
绵羊 IL-1β 和 IL-6 通过饱和转运穿过小鼠 BBB。鼠同系物对转运的抑制作用表明，两种物种都使用相同的转运机制。相反，绵羊细胞因子不能显著抑制鼠细胞因子的转运表明，小鼠 BBB 对绵羊细胞因子的亲和力低于鼠细胞因子。对中枢神经系统发病机制的新型动物模型的开发，了解种属保守的 BBB 转运机制可能会有所帮助。
