Santos L, Hall P, Metz C, Bucala R, Morand E F
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Australia.
Clin Exp Immunol. 2001 Feb;123(2):309-14. doi: 10.1046/j.1365-2249.2001.01423.x.
(MIF) is a broad-spectrum proinflammatory cytokine implicated in human rheumatoid arthritis. The synthesis of MIF by synovial cells is stimulated by glucocorticoids, and previous studies suggest that MIF antagonizes the anti-inflammatory effects of glucocorticoids. This has not been established in a model of arthritis. We wished to test the hypothesis that MIF can act to reverse the anti-inflammatory effects of glucocorticoids in murine antigen-induced arthritis (AIA). Cutaneous DTH reactions and AIA were induced by intradermal injection and intra-articular injection, respectively, of methylated bovine serum albumin in presensitized mice. Animals were treated with anti-MIF MoAbs, recombinant MIF, and/or dexamethasone (DEX). Skin thickness of DTH reactions was measured with callipers and arthritis severity was measured by blinded quantitative histological assessment of synovial cellularity. Cutaneous DTH to the disease-initiating antigen was significantly inhibited by anti-MIF MoAb treatment (P < 0.001). AIA was also significantly inhibited by anti-MIF MoAb (P < 0.02). DEX treatment induced a dose-dependent inhibition of AIA, which was significant at 0.2 mg/kg (P < 0.05). MIF treatment reversed the effect of therapeutic DEX on AIA (P < 0.001). DEX also significantly inhibited DTH reactions (P < 0.05) but rMIF had no effect on this effect of DEX. DTH and AIA are MIF-dependent models of inflammation and arthritis. The reversal of glucocorticoid suppression of AIA by MIF supports the concept that MIF is a counter-regulator of glucocorticoid control of synovial inflammation. Although DTH was observed to be MIF-dependent and glucocorticoid-sensitive, rMIF had no reversing effect on the suppression of DTH by glucocorticoids. This suggests that inflammatory processes in specific tissues may respond differently to MIF in the presence of glucocorticoids.
巨噬细胞移动抑制因子（MIF）是一种与人类类风湿性关节炎相关的广谱促炎细胞因子。滑膜细胞合成MIF受糖皮质激素刺激，先前的研究表明MIF可拮抗糖皮质激素的抗炎作用。但这在关节炎模型中尚未得到证实。我们希望验证MIF可逆转糖皮质激素对小鼠抗原诱导性关节炎（AIA）抗炎作用的假说。在预先致敏的小鼠中，分别通过皮内注射和关节内注射甲基化牛血清白蛋白诱导皮肤迟发型超敏反应（DTH）和AIA。动物接受抗MIF单克隆抗体、重组MIF和/或地塞米松（DEX）治疗。用卡尺测量DTH反应的皮肤厚度，通过对滑膜细胞数量进行盲法定量组织学评估来测量关节炎严重程度。抗MIF单克隆抗体治疗可显著抑制针对引发疾病抗原的皮肤DTH反应（P<0.001）。抗MIF单克隆抗体也可显著抑制AIA（P<0.02）。DEX治疗可诱导对AIA的剂量依赖性抑制，在0.2mg/kg时具有显著性（P<0.05）。MIF治疗可逆转治疗剂量的DEX对AIA的作用（P<0.001）。DEX也可显著抑制DTH反应（P<0.05），但重组MIF对DEX的这种作用没有影响。DTH和AIA是依赖MIF的炎症和关节炎模型。MIF逆转糖皮质激素对AIA的抑制作用支持了MIF是糖皮质激素控制滑膜炎症的反调节因子这一概念。尽管观察到DTH依赖MIF且对糖皮质激素敏感，但重组MIF对糖皮质激素抑制DTH没有逆转作用。这表明在存在糖皮质激素的情况下，特定组织中的炎症过程对MIF的反应可能不同。
