Liu Song, Xu Guo-Ying, Johnson Kathia M, Echetebu Clement, Ye Zaiming Sam, Hulsebosch Claire E, McAdoo David J
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA.
Brain Res. 2008 Sep 22;1231:63-74. doi: 10.1016/j.brainres.2008.07.035. Epub 2008 Jul 19.
Elevation of extracellular glutamate contributes to cell death and functional impairments generated by spinal cord injury (SCI), in part through the activation of the neurotoxic cytokine interleukin-1beta (IL-1beta). This study examines the participation of IL-1beta and its regulation by the endogenous interleukin-1 receptor antagonist (IL-1ra) in glutamate toxicity following SCI. Glutamate, glutamatergic agonists and SCI had similar effects on levels of IL-1beta and IL-1ra. Following spinal cord contusion or exposure to elevated glutamate, concentrations of IL-1beta first increased as IL-1ra decreased, and both then changed in the opposite directions. Applying the glutamate agonists NMDA and S-AMPA to the spinal cord caused changes in IL-1beta and IL-1ra levels very similar to those produced by contusion and glutamate. The glutamate antagonists MK801 and NBQX blocked the glutamate-induced changes in IL-1beta and IL-1ra levels. Administering IL-1beta elevated IL-1ra, and administering IL-1ra depressed IL-1beta levels. Infusing IL-beta into the spinal cord impaired locomotion, and infusing IL-1ra improved recovery from glutamate-induced motor impairments. We hypothesize that elevating IL-1ra opposes the damage caused by IL-1beta in SCI by reducing IL-1beta levels as well as by blocking binding of IL-1beta to its receptor. Our results demonstrate that IL-1beta contributes to glutamate damage following SCI; blocking IL-1beta may usefully counteract glutamate toxicity.
细胞外谷氨酸水平升高会导致脊髓损伤（SCI）引起的细胞死亡和功能障碍，部分原因是通过激活神经毒性细胞因子白细胞介素-1β（IL-1β）。本研究探讨了IL-1β的参与及其受内源性白细胞介素-1受体拮抗剂（IL-1ra）调节在SCI后谷氨酸毒性中的作用。谷氨酸、谷氨酸能激动剂和SCI对IL-1β和IL-1ra水平有相似的影响。脊髓挫伤或暴露于升高的谷氨酸后，IL-1β浓度首先随着IL-1ra降低而升高，然后两者朝相反方向变化。将谷氨酸激动剂N-甲基-D-天冬氨酸（NMDA）和S-氨基-3-羟基-5-甲基异恶唑-4-丙酸（S-AMPA）应用于脊髓引起的IL-1β和IL-1ra水平变化与挫伤和谷氨酸引起的变化非常相似。谷氨酸拮抗剂地卓西平马来酸盐（MK801）和2,3-二羟基-6-硝基-7-磺酰基苯并[f]喹喔啉-2,3-二酮（NBQX）阻断了谷氨酸诱导的IL-1β和IL-1ra水平变化。给予IL-1β会升高IL-1ra，给予IL-1ra会降低IL-1β水平。向脊髓内注入IL-β会损害运动能力，注入IL-1ra可改善谷氨酸诱导的运动功能障碍的恢复。我们推测，升高IL-1ra可通过降低IL-1β水平以及阻断IL-1β与其受体的结合来对抗SCI中IL-1β造成的损伤。我们的结果表明，IL-1β在SCI后导致谷氨酸损伤；阻断IL-1β可能有效地对抗谷氨酸毒性。
