Oh J W, Van Wagoner N J, Rose-John S, Benveniste E N
Department of Cell Biology, University of Alabama, Birmingham 35294, USA.
J Immunol. 1998 Nov 1;161(9):4992-9.
Adhesion molecules such as VCAM-1 and ICAM-1 are increased in the central nervous system (CNS) during inflammatory responses and contribute to extravasation of leukocytes across the blood-brain barrier (BBB) and into CNS parenchyma. Astrocytes contribute to the structural integrity of the BBB and can be induced to express VCAM-1 and ICAM-1 in response to cytokines such as TNF-alpha, IL-1beta, and IFN-gamma. In this study, we investigated the influence of IL-6 on astroglial adhesion molecule expression. IL-6, the soluble form of the IL-6R (sIL-6R), or both IL-6 plus sIL-6R, had no effect on VCAM-1 or ICAM-1 gene expression. Interestingly, the IL-6/sIL-6R complex inhibited TNF-alpha-induced VCAM-1 gene expression but did not affect TNF-alpha-induced ICAM-1 expression. The inhibitory effect of IL-6/sIL-6R complex was reversed by the inclusion of anti-IL-6R and gp130 Abs, demonstrating the specificity of the response. A highly active fusion protein of sIL-6R and IL-6, covalently linked by a flexible peptide, which is designated H-IL-6, also inhibited TNF-alpha-induced VCAM-1 expression. sIL-6R alone was an effective inhibitor of TNF-alpha-induced VCAM-1 due to endogenous IL-6 production. These results indicate that the IL-6 system has an unexpected negative effect on adhesion molecule expression in glial cells and may function as an immunosuppressive cytokine within the CNS.
在炎症反应期间，诸如血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）等黏附分子在中枢神经系统（CNS）中表达增加，有助于白细胞穿过血脑屏障（BBB）并渗入CNS实质。星形胶质细胞有助于BBB的结构完整性，并可被诸如肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和干扰素-γ（IFN-γ）等细胞因子诱导表达VCAM-1和ICAM-1。在本研究中，我们调查了白细胞介素-6（IL-6）对星形胶质细胞黏附分子表达的影响。IL-6、IL-6受体的可溶性形式（sIL-6R）或IL-6加sIL-6R两者，对VCAM-1或ICAM-1基因表达均无影响。有趣的是，IL-6/sIL-6R复合物抑制TNF-α诱导的VCAM-1基因表达，但不影响TNF-α诱导的ICAM-1表达。加入抗IL-6R和gp130抗体可逆转IL-6/sIL-6R复合物的抑制作用，证明了反应的特异性。一种由柔性肽共价连接的sIL-6R和IL-6的高活性融合蛋白，命名为H-IL-6，也抑制TNF-α诱导的VCAM-1表达。由于内源性IL-6的产生，单独的sIL-6R是TNF-α诱导的VCAM-1的有效抑制剂。这些结果表明，IL-6系统对神经胶质细胞黏附分子的表达具有意想不到的负面影响，并且可能在CNS内作为一种免疫抑制细胞因子发挥作用。
