Oliver S J, Freeman S L, Corral L G, Ocampo C J, Kaplan G
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
Clin Exp Immunol. 1999 Nov;118(2):315-21. doi: 10.1046/j.1365-2249.1999.01039.x.
The cytokine tumour necrosis factor-alpha (TNF-alpha) has been implicated in the aetiology of rheumatoid arthritis in humans as well as of experimental arthritis in rodents. Thalidomide, and to a greater extent the new thalidomide analogue CC1069, inhibit monocyte TNF-alpha production both in vitro and in vivo. The aim of the present study is to establish whether these drugs block production of TNF-alpha as well as IL-2 by rat leucocytes and whether this inhibition affects the development of rat adjuvant arthritis (AA). Cultured splenocytes were stimulated with either lipopolysaccharide (LPS) or concanavalin A (Con A) in the presence of thalidomide, CC1069, or solvent, and the production of TNF-alpha and IL-2 were compared. Next, adjuvant was injected into the base of the tail of rats without or with daily intraperitoneal injections with 100-200 mg/kg per day thalidomide or 50-200 mg/kg per day CC1069. Disease activity, including ankle swelling, hind limb radiographic and histological changes, weight gain, and ankle joint cytokine mRNA levels, were monitored. CC1069, but not the parent drug thalidomide, inhibited in vitro production of TNF-alpha and IL-2 by stimulated splenocytes in a dose-dependent manner. In vivo, a dose-dependent suppression of AA disease activity occurred in the CC1069-treated animals. In contrast, thalidomide-treated rats experienced comparable arthritis severity to placebo-treated animals. There was also a reduction in TNF-alpha and IL-2 mRNA levels in the ankle joints of CC1069-treated rats compared with thalidomide- and placebo-treated arthritic rats. Early initiation of CC1069 treatment suppressed AA inflammation more efficiently than delayed treatment. We conclude that thalidomide, which did not suppress TNF-alpha or IL-2 production in vitro by Lewis rat cells, did not suppress development of rat AA. However, the development of rat AA can be blocked by the thalidomide analogue CC1069, which is an efficient inhibitor of TNF-alpha production and IL-2 in vitro.
细胞因子肿瘤坏死因子-α（TNF-α）被认为与人类类风湿性关节炎以及啮齿动物实验性关节炎的病因有关。沙利度胺，以及在更大程度上新型沙利度胺类似物CC1069，在体外和体内均能抑制单核细胞TNF-α的产生。本研究的目的是确定这些药物是否会阻断大鼠白细胞产生TNF-α以及IL-2，以及这种抑制作用是否会影响大鼠佐剂性关节炎（AA）的发展。在存在沙利度胺、CC1069或溶剂的情况下，用脂多糖（LPS）或伴刀豆球蛋白A（Con A）刺激培养的脾细胞，并比较TNF-α和IL-2的产生。接下来，在大鼠尾部基部注射佐剂，部分大鼠每日腹腔注射100 - 200mg/kg的沙利度胺或50 - 200mg/kg的CC1069，部分大鼠不注射。监测疾病活动情况，包括踝关节肿胀、后肢X线和组织学变化、体重增加以及踝关节细胞因子mRNA水平。CC1069而非母体药物沙利度胺，以剂量依赖的方式抑制了刺激的脾细胞体外产生TNF-α和IL-2。在体内，CC1069治疗的动物中出现了剂量依赖性的AA疾病活动抑制。相比之下（此处原文有误，根据前文及逻辑，应是“相比之下，沙利度胺治疗的大鼠与安慰剂治疗的动物经历了相当的关节炎严重程度”），沙利度胺治疗的大鼠与安慰剂治疗的动物经历了相当的关节炎严重程度。与沙利度胺和安慰剂治疗的关节炎大鼠相比，CC1069治疗的大鼠踝关节中TNF-α和IL-2 mRNA水平也有所降低。CC1069治疗的早期启动比延迟治疗更有效地抑制了AA炎症。我们得出结论，沙利度胺在体外不抑制Lewis大鼠细胞产生TNF-α或IL-2，也不抑制大鼠AA的发展。然而，大鼠AA的发展可被沙利度胺类似物CC1069阻断，CC1069在体外是TNF-α产生和IL-2的有效抑制剂。
