Department of Orthopaedic Surgery, Tokyo Women's Medical University, Medical Center East, 2-1-10 Nishiogu, Arakawa, Tokyo, Japan.
Clin Rheumatol. 2011 Nov;30(11):1407-13. doi: 10.1007/s10067-011-1833-z. Epub 2011 Sep 10.
To investigate the histological changes of mitogen-activated protein kinase (MAPK) in synovium with tocilizumab in rheumatoid arthritis (RA), synovial tissue samples were assessed from ten methotrexate (MTX)-treated RA patients for control and ten tocilizumab with MTX-treated RA patients. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cell), CD20 (B cell), CD68 (macrophage), vascular endothelial growth factor (VEGF), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK [extracellular signal-regulated kinase (ERK) 1/ERK2], and phospho-c-Jun N-terminal kinase (JNK). H&E staining showed that there is a significant difference of cell proliferation; however, there is no change of hypervascularity in the synovium between both groups. An immunohistochemical examination showed that the decrease of CD29 (β-1 integrin) and JNK was found significant, while ERK was increased in the tocilizumab group. CD20, B-lymphocyte, was decreased in the tocilizumab group compared with the MTX group significantly. IL-6 was completely blocked in the patients who received tocilizumab. TNF-α was similarly expressed in the interstitial cells of synovium of patients in both groups. MMP-3 and CD68 were similarly expressed on the surface of synovium. VEGF was less expressed in both groups. These findings indicate that the inhibition of CD20, CD29, and JNK in MAPK may be involved in the efficacy of tocilizumab compared with MTX treatment in RA.
为了研究在类风湿关节炎（RA）中，托珠单抗对丝裂原活化蛋白激酶（MAPK）的组织学变化，我们评估了来自十名接受甲氨蝶呤（MTX）治疗的 RA 患者的滑膜组织样本（对照组）和十名接受托珠单抗联合 MTX 治疗的 RA 患者的滑膜组织样本。使用苏木精和伊红（H&E）染色观察滑膜，并通过免疫组织化学分析肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、基质金属蛋白酶-3（MMP-3）、CD4（T 细胞）、CD20（B 细胞）、CD68（巨噬细胞）、血管内皮生长因子（VEGF）、CD29（β-1 整合素）、磷酸化 p38 MAPK（Tyr180/Tyr182）、磷酸化 p44/42 MAPK [细胞外信号调节激酶（ERK）1/ERK2]和磷酸化 c-Jun N 末端激酶（JNK）的表达。H&E 染色显示细胞增殖有显著差异，但两组滑膜的高血管生成无变化。免疫组织化学检查显示，CD29（β-1 整合素）和 JNK 的减少有显著意义，而 ERK 在托珠单抗组中增加。与 MTX 组相比，托珠单抗组的 CD20、B 淋巴细胞减少。IL-6 在接受托珠单抗治疗的患者中完全被阻断。两组患者滑膜间质细胞中 TNF-α表达相似。MMP-3 和 CD68 在滑膜表面表达相似。两组 VEGF 表达均减少。这些发现表明，与 MTX 治疗相比，MAPK 中 CD20、CD29 和 JNK 的抑制可能参与了托珠单抗在 RA 中的疗效。
