Sumariwalla P F, Malfait A M, Feldmann M
Kennedy Institute of Rheumatology, Imperial College London, UK.
Clin Exp Immunol. 2004 Apr;136(1):67-75. doi: 10.1111/j.1365-2249.2004.02421.x.
We investigated the therapeutic potential of P-selectin glycoprotein ligand (PSGL)-1 in established collagen-induced arthritis (CIA) in DBA/1 mice. PSGL-1 is the high-affinity specific ligand for P-selectin and is thus important in cell recruitment to inflammatory sites. I-316 PSGL-1 or rPSGL-1Ig fusion protein were administered to mice after the onset of clinical arthritis for 10 days, and the effect of treatment on both clinical and histopathological progression of disease was studied. It was found that both PSGL-1 biologicals effectively suppressed progression of clinical arthritis, and this was accompanied by protection against damage of joint tissues. We sought to investigate a mechanism underlying the effect of rPSGL-1Ig on the reduction of clinical arthritis. Blockade of PSGL-1/P-selectin interaction blocks recruitment of leucocytes, thus we observed a notable reduction in viable cell numbers of synoviocytes from rPSGL-1Ig treated mice. In view of this finding we suspected an effect of treatment on the production of pro-inflammatory mediators such as bioactive tumour necrosis factor-alpha (TNF) in synovial membrane ex vivo cell cultures. Production of TNF was reduced in arthritic mice that had been treated with rPSGL-1Ig. To further investigate the mechanism of rPSGL-1Ig, we explored the possibility that PSGL-1 might also have a direct signalling effect on TNF release from inflammatory cells. Thus synoviocyte cultures from arthritic mice were incubated with rPSGL-1Ig. A significant reduction in the spontaneous bioactive TNF release from these cultures was noted. We therefore confirmed these surprising findings using cultures of a mouse macrophage like cell line RAW 264.7, stimulated by LPS. Our results indicate that both forms of PSGL-1 have significant therapeutic effects in CIA murine model of RA. The mechanism of action involves reduced cellularity of synovium as anticipated, along with a reduction in TNF production from inflammatory cells in the synovium. The latter mechanism needs further mechanistic analysis.
我们研究了P-选择素糖蛋白配体（PSGL）-1在已建立胶原诱导性关节炎（CIA）的DBA/1小鼠中的治疗潜力。PSGL-1是P-选择素的高亲和力特异性配体，因此在细胞募集到炎症部位中起重要作用。在临床关节炎发作10天后，将I-316 PSGL-1或rPSGL-1Ig融合蛋白给予小鼠，并研究治疗对疾病临床和组织病理学进展的影响。发现两种PSGL-1生物制剂均有效抑制临床关节炎的进展，并且这伴随着对关节组织损伤的保护。我们试图研究rPSGL-1Ig减轻临床关节炎作用的潜在机制。PSGL-1/P-选择素相互作用的阻断会阻止白细胞的募集，因此我们观察到来自rPSGL-1Ig处理小鼠的滑膜细胞活细胞数量显著减少。鉴于这一发现，我们怀疑治疗对体外滑膜细胞培养物中促炎介质如生物活性肿瘤坏死因子-α（TNF）的产生有影响。用rPSGL-1Ig治疗的关节炎小鼠中TNF的产生减少。为了进一步研究rPSGL-1Ig的作用机制，我们探讨了PSGL-1可能对炎症细胞释放TNF也有直接信号作用的可能性。因此，将来自关节炎小鼠的滑膜细胞培养物与rPSGL-1Ig一起孵育。注意到这些培养物中自发生物活性TNF释放显著减少。因此，我们使用脂多糖刺激的小鼠巨噬细胞样细胞系RAW 264.7培养物证实了这些惊人的发现。我们的结果表明，两种形式的PSGL-1在类风湿性关节炎的CIA小鼠模型中均具有显著的治疗作用。作用机制包括如预期的滑膜细胞数量减少，以及滑膜中炎症细胞TNF产生的减少。后一种机制需要进一步的机制分析。
