CERAMIDE,APOPTOSIS-INDUCING SECOND-MESSENGER,USED IN THE TREATMENT OF LUPUS-PRONE MODEL MICE

与Fas配体结合后，细胞表面Fas在淋巴细胞内传递凋亡信号，Cerarnide被认为是这一途径中的第二信使。我们去年报道，口服一种与神经酰胺结构非常相似的新型免疫抑制剂FTY72O，成功地改善了肾小球肾炎，并延长了狼疮性MRL-LPR/LPR小鼠的存活率。鉴于长链神经酰胺在体外不能穿透细胞膜并诱导细胞凋亡，本研究选择了C2-神经酰胺作为研究对象。给15只4月龄MRL-LPR/LPR小鼠灌胃2mgfkg体重的C2-神经酰胺，每周三次。将相同数量的MRL-LPR/LPR小鼠单独给予橄榄油作为阴性对照或给予地塞米松(2 mg/kg)作为阳性对照进行治疗。在8月龄时，经C2-神经酰胺治疗的MRL-LPR/LPR小鼠表现出较长的存活曲线，具有CD^&lt；3&gt；cd^&lt；4--gt；cd^&lt；8-&gt；表型的T细胞数量减少，血清抗DNA抗体水平低于单纯橄榄油治疗组。这些参数均具有统计学意义。经C2-神经酰胺处理的小鼠肾小球内沉积的免疫球蛋白远远少于单独使用橄榄油的小鼠。口服C2-神经酰胺引起的上述改善水平与地塞米松相当。未观察到全身抗Fas抗体和地塞米松治疗的严重副作用--肝损害和高血糖，C2-神经酰胺可能是一种副作用较小的治疗方案，值得进一步关注。

Upon ligation with Fas-ligand, cell-surface Fas transmits apoptosis-signals in lymphocytes and cerarnide is considered to act as a second messenger in this pathway. We reported last year that oral administration of a novel immunosuppressant FTY72O, which has a very close structural similarity with ceramide, successfully improved glomerulonephritis and prolonged survival rates of lupusprone MRL-lpr/lpr mice. The purpose of the study this year, therefore, is to examine whether ceramide itself could be used for treatment of MRL-lpr/lpr mice when administered orally.Because ceramides with long side-chains can not penetrate cell membranes and induce apoptosis in vitro, we selected cell-permeable C2-ceramide in this study. Two mgfkg body weight of C2-ceramide dissolved in olive-oil were administered orally three times a week to 15 MRL-lpr/lpr mice of 4-month old. The same number of MRL-lpr/lpr mice was received either olive-oil alone as a negative control or dexamethasone (2 mg/kg) as a positive control for treatment. Anti-DNA antibody titer in sera, survival curve and renal pathology were examined for the efficacy of the treatments.At the age of eight months, MRL-lpr/lpr mice treated with C2-ceramide showed a longer survival curve, decreased number of T cells with a CD^<3+>CD^<4->CD^<8-> phenotype, and a lower level of serum anti-DNA antibody than those treated with olive-oil alone. These parameters were all statistically signficant. IgG deposited in glomeruli from mice treated with C2-ceramide was far less than that from mice administered with olive-oil alone. Level of these mprovements induced by oral C2-ceramide was almost comparable with that induced by dexamethasone. Liver damage and hyperglycemia which were desasterous side-effects of systemic anti-Fas antibody and dexamethasone administration, respectively, were not observed.C2-ceramide seems to deserve further attention for a possible therapeutic regimen with less side-effect.