Nagy S E, Andersson J P, Andersson U G
Department of Infectious Diseases, Karolinska Institute, Stockholm, Sweden.
Immunopharmacology. 1993 Jul-Aug;26(1):11-20. doi: 10.1016/0162-3109(93)90062-u.
The effects of the immunosuppressant mycophenolate mofetil (MPAM, RS-61443) on cytokine production at the single cell level were assessed using in vitro activated human mononuclear cells. Cytokine production was studied with UV microscopy of fixed and permeabilized cells stained with cytokine specific monoclonal antibodies (mAbs). The cytokines evaluated included interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10 interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), TNF-beta, and granulocyte macrophage-colony stimulating factor (GM-CSF). MPAM exhibited a marked antiproliferative effect without cytotoxicity in all mononuclear cell cultures. Six to 24 hours after stimulation with the superantigen Staphylococcus aureus enterotoxin A (SEA), most cytokine production was unaffected by MPAM at therapeutic concentrations (10(-6) M), with the exception of GM-CSF. In contrast, by 48 h after antigen activation, MPAM significantly inhibited all studied cytokine production (p < 0.05). Cyclosporin A (CsA), used as a control at a concentration of 100 ng/ml, inhibited production of all studied cytokines, at all time points. Monokine production after lipopolysaccharide (LPS) stimulation was unaffected by MPAM. Similarly, the production of most of the cytokines studied after mitogen stimulation with phorbol ester (PMA) plus calcium ionophore (ionomycin) was not affected by MPAM, in comparison to CsA which demonstrated significant inhibition of all cytokines tested under these conditions. However, a late inhibitory effect on IL-3 production was seen by MPAM at 48 h after mitogenic stimulation. Further observations are required to explain the divergent results on cytokine production by MPAM in superantigen-activated and mitogen-activated human mononuclear cells.
使用体外活化的人单核细胞评估免疫抑制剂霉酚酸酯（MPAM，RS - 61443）在单细胞水平对细胞因子产生的影响。通过用细胞因子特异性单克隆抗体（mAb）染色的固定和通透细胞的紫外显微镜研究细胞因子的产生。评估的细胞因子包括白细胞介素 - 1α（IL - 1α）、IL - 1β、IL - 2、IL - 3、IL - 4、IL - 5、IL - 6、IL - 10、干扰素γ（IFN - γ）、肿瘤坏死因子α（TNF - α）、TNF - β和粒细胞巨噬细胞集落刺激因子（GM - CSF）。在所有单核细胞培养物中，MPAM表现出显著的抗增殖作用且无细胞毒性。在用超抗原金黄色葡萄球菌肠毒素A（SEA）刺激6至24小时后，治疗浓度（10⁻⁶ M）的MPAM对大多数细胞因子的产生没有影响，但GM - CSF除外。相反，在抗原激活后48小时，MPAM显著抑制所有研究的细胞因子产生（p < 0.05）。浓度为100 ng/ml用作对照的环孢素A（CsA）在所有时间点均抑制所有研究的细胞因子产生。脂多糖（LPS）刺激后的单核因子产生不受MPAM影响。同样，与在这些条件下对所有测试细胞因子均有显著抑制作用的CsA相比，在用佛波酯（PMA）加钙离子载体（离子霉素）进行丝裂原刺激后，大多数研究的细胞因子产生不受MPAM影响。然而，在有丝分裂原刺激后48小时，MPAM对IL - 3产生有后期抑制作用。需要进一步观察来解释MPAM在超抗原激活和丝裂原激活的人单核细胞中对细胞因子产生的不同结果。
