Bober L A, Rojas-Triana A, Jackson J V, Leach M W, Manfra D, Narula S K, Grace M J
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Arthritis Rheum. 2000 Dec;43(12):2660-7. doi: 10.1002/1529-0131(200012)43:12<2660::AID-ANR5>3.0.CO;2-4.
To assess the capacity of interleukin-4 (IL-4) and IL-10 to block polymorphonuclear neutrophil (PMN) activation in an ex vivo human model system, and to confirm their effect on neutrophil function in an animal model of arthritis.
The ex vivo phagocytic capacity of cytokine-activated human PMNs was assessed by use of assays for measuring the ingestion of heat-killed yeast and by subsequent hexose-monophosphate shunt activation using nitroblue tetrazolium reduction. The in vivo activity of IL-4 and IL-10 was measured using a rat adjuvant arthritis model in which the mycobacterial antigen concentration was titrated to modify disease intensity.
IL-4 and IL-10 suppressed the ex vivo activation state of interferon-gamma- and tumor necrosis factor alpha-activated human neutrophils. In the rat adjuvant arthritis model, treatment with systemic murine IL-10 (mIL-10) effectively suppressed all disease parameters in rats that received the lower concentrations of mycobacteria, whereas systemic mIL-4 was effective against even the most severe disease. Both cytokines were effective in lowering the absolute PMN cell number recovered and the PMN activation state in the joint synovia. We also observed lower levels of the messenger RNA transcript for CINC protein (cytokine-induced neutrophil chemoattractant; a rat homolog for human IL-8) in the synovia.
IL-10 is an effective antiarthritic agent and has a major effect on the presence and function of PMNs in the joint synovia when disease intensity is not severe. IL-4 has an inhibitory profile that is similar to that of IL-10, but is effective in modifying even the most severe disease. Both cytokines reduced the phagocytic activation of human PMNs in response to proinflammatory cytokines. These data demonstrate that IL-4 and IL-10 can exert powerful regulatory effects on neutrophil function that translate into a therapeutic response in a disease model of arthritis. Treatment with these cytokines alone or in combination may therefore be very useful in the management of patients with rheumatoid arthritis.
在体外人模型系统中评估白细胞介素 -4（IL -4）和IL -10阻断多形核中性粒细胞（PMN）活化的能力，并在关节炎动物模型中证实它们对中性粒细胞功能的影响。
通过测量热灭活酵母摄取的试验以及随后使用硝基蓝四氮唑还原进行的磷酸己糖旁路激活，评估细胞因子激活的人PMN的体外吞噬能力。使用大鼠佐剂性关节炎模型测量IL -4和IL -10的体内活性，在该模型中滴定分枝杆菌抗原浓度以改变疾病强度。
IL -4和IL -10抑制了干扰素 -γ和肿瘤坏死因子α激活的人中性粒细胞的体外活化状态。在大鼠佐剂性关节炎模型中，用全身性鼠IL -10（mIL -10）治疗有效地抑制了接受较低浓度分枝杆菌的大鼠的所有疾病参数，而全身性mIL -4即使对最严重的疾病也有效。两种细胞因子均有效地降低了关节滑膜中回收的PMN绝对细胞数和PMN活化状态。我们还观察到滑膜中CINC蛋白（细胞因子诱导的中性粒细胞趋化因子；人IL -8的大鼠同源物）的信使RNA转录水平较低。
当疾病强度不严重时，IL -10是一种有效的抗关节炎药物，对关节滑膜中PMN的存在和功能有主要影响。IL -4具有与IL -10相似的抑制作用，但即使对最严重的疾病也能有效改善。两种细胞因子均降低了人PMN对促炎细胞因子的吞噬激活。这些数据表明，IL -4和IL -10可对中性粒细胞功能发挥强大的调节作用，并在关节炎疾病模型中转化为治疗反应。因此，单独或联合使用这些细胞因子治疗可能对类风湿性关节炎患者的管理非常有用。
