Kitani A, Nakashima N, Izumihara T, Inagaki M, Baoui X, Yu S, Matsuda T, Matsuyama T
Department of Immunology, School of Medicine, Kagoshima University, Japan.
J Immunol. 1998 Nov 1;161(9):4931-8.
It has been shown that cells with high affinity very late Ag (VLA)-integrins have up-regulated expression of a beta1-subunit epitope, which is detected by 15/7 mAb. In this study, we demonstrate that soluble VCAM-1 (sVCAM-1) exhibits chemotactic activity of T cells with high affinity VLA-4 against VCAM-1, such as Jurkat T cells and IL-2-dependent T cells. Moreover, we found that T cells in the synovial fluid show high basal migration in the absence of sVCAM-1, compared with peripheral blood T cells in patients with rheumatoid arthritis. Among T cells in the synovial fluid, CD45RO+ memory T cells, in response to sVCAM-1, showed a much higher than basal migratory response when compared with CD45RA+ naive cells, while no significant difference was observed between CD4+ and CD8+ T cells. The chemotactic activity of sVCAM-1 is inhibited in the presence of anti-VCAM-1 and anti-VLA-4, which interfered with the binding between VCAM-1 and VLA-4. Inhibition studies using various kinase inhibitors (C3 exoenzyme, KN62, and H7) show that Rho, Ca2+/calmodulin-dependent kinase II, and protein kinase C are involved in signal transduction in sVCAM-1-induced chemotaxis, respectively, whereas tyrosine kinase seems to play a lesser role, since genistein showed only partial inhibition of T cell chemotaxis. Western blot analysis using an anti-phospho-serine mAb (MO82) reveals that Ser82 in the vimentin is phosphorylated specifically by Ca2+/calmodulin-dependent kinase II through sVCAM-1 activation in the IL-2 dependent T cells. Collectively, by inducing migration and recruitment of T cells through several kinase activations, sVCAM-1 contributes to the development of the inflammation of synovial lesion.
研究表明，具有高亲和力极晚期抗原（VLA）整合素的细胞，其β1亚单位表位的表达上调，可被15/7单克隆抗体检测到。在本研究中，我们证明可溶性血管细胞黏附分子-1（sVCAM-1）对具有高亲和力VLA-4的T细胞，如Jurkat T细胞和白细胞介素-2依赖型T细胞，表现出针对VCAM-1的趋化活性。此外，我们发现与类风湿性关节炎患者的外周血T细胞相比，滑液中的T细胞在无sVCAM-1时显示出高基础迁移率。在滑液中的T细胞中，与CD45RA+初始细胞相比，CD45RO+记忆T细胞对sVCAM-1的反应显示出比基础迁移反应高得多的迁移反应，而CD4+和CD8+T细胞之间未观察到显著差异。在抗VCAM-1和抗VLA-4存在的情况下，sVCAM-1的趋化活性受到抑制，这干扰了VCAM-1与VLA-4之间的结合。使用各种激酶抑制剂（C3外切酶、KN62和H7）的抑制研究表明，Rho、Ca2+/钙调蛋白依赖性激酶II和蛋白激酶C分别参与sVCAM-1诱导趋化作用的信号转导，而酪氨酸激酶似乎起的作用较小，因为染料木黄酮仅部分抑制T细胞趋化作用。使用抗磷酸丝氨酸单克隆抗体（MO82）的蛋白质印迹分析表明，波形蛋白中的Ser82在白细胞介素-2依赖型T细胞中通过sVCAM-1激活被Ca2+/钙调蛋白依赖性激酶II特异性磷酸化。总的来说，可以通过几种激酶激活诱导T细胞的迁移和募集，sVCAM-1促进滑膜病变炎症的发展。
