Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury
Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury
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DOI：
10.1002/jnr.20044
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发表时间：
2004-04-15
影响因子：
4.2
通讯作者：
Okano, H
中科院分区：
文献类型：
--
作者：
Okada, S;Nakamura, M;Okano, H
内源性神经干/祖细胞（NSPCs）最近被证明只分化成星形胶质细胞，参与脊髓损伤（SCI）后胶质瘢痕形成的细胞。脊髓的微环境，特别是在损伤部位急性期急剧增加的炎性细胞因子，被认为是SCI后神经元分化抑制机制的重要原因。白细胞介素-6（IL-6）已被证明在体外通过JAK/STAT途径选择性地诱导NSPCs进行星形胶质细胞分化，也已被证明作为促炎细胞因子发挥关键作用，并与SCI中的继发性组织损伤相关。在这项研究中，我们评估了大鼠抗小鼠IL-6受体单克隆抗体（MR 16 - 1）在治疗急性脊髓损伤小鼠的疗效。在用改良的NYU撞击器造成挫伤性SCI后，立即向小鼠腹膜内注射单剂量的MR 16 - 1（100 μ g/g体重），组织学评估损伤，并评价功能恢复。MR16 - 1不仅在体外抑制了IL-6信号对星形胶质细胞分化的促进作用，而且在体内抑制了SCI后星形胶质细胞增生的发展。MR16 - 1还减少了侵入的炎性细胞的数量和结缔组织瘢痕形成的严重程度。此外，与对照小鼠相比，我们观察到用MR16 - 1处理的小鼠的显著功能恢复。这些发现表明，在SCI的急性期中和IL-6信号转导是SCI治疗的一个有吸引力的选择。(C)2004 Wiley-Liss，Inc.
Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 mug/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI. (C) 2004 Wiley-Liss, Inc.