Yang Y, Hutchinson P, Morand E F
Monash University, Melbourne, Victoria, Australia.
Arthritis Rheum. 1999 Jul;42(7):1538-44. doi: 10.1002/1529-0131(199907)42:7<1538::AID-ANR29>3.0.CO;2-3.
Annexin I is an endogenous antiinflammatory mediator, expressed in rheumatoid arthritis (RA) synovium, the contribution of which to autoregulation of the synovial inflammatory response has not been examined in models of RA. We investigated the antiinflammatory role of annexin I in rat adjuvant arthritis.
Rats with adjuvant-induced arthritis (AIA) were treated with a specific anti-annexin I monoclonal antibody (mAb), isotype control IgG, and/or dexamethasone. Clinical outcomes and synovial synthesis of tumor necrosis factor alpha (TNFalpha), prostaglandin E2 (PGE2), and nitric oxide were examined, and annexin I expression was assessed by flow cytometry and reverse transcription-polymerase chain reaction.
Anti-annexin I mAb reversed the effects of dexamethasone on the clinical features of AIA and exacerbated AIA in the absence of exogenous glucocorticoid. Clinical exacerbation of AIA by anti-annexin I mAb was accompanied by significantly increased synovial TNFalpha and PGE2, suggesting that annexin I tonically inhibits the production of these mediators. Anti-annexin I mAb treatment was associated with significantly reduced leukocyte intracellular annexin I, despite increased annexin I messenger RNA expression, consistent with a depletion effect of extracellular mAb via the cell surface.
Annexin I is a key endogenous inhibitory mediator of arthritis via mechanisms that include inhibition of cytokine and effector molecule production. Moreover, a synthesis-independent depletion of intracellular annexin I by extracellular antibody supports the hypothesis that externalization of annexin I is involved in its mode of action.
膜联蛋白I是一种内源性抗炎介质，在类风湿关节炎（RA）滑膜中表达，但其对滑膜炎症反应自身调节的作用尚未在RA模型中进行研究。我们研究了膜联蛋白I在大鼠佐剂性关节炎中的抗炎作用。
用特异性抗膜联蛋白I单克隆抗体（mAb）、同型对照IgG和/或地塞米松治疗佐剂诱导性关节炎（AIA）大鼠。检测临床结局以及肿瘤坏死因子α（TNFα）、前列腺素E2（PGE2）和一氧化氮的滑膜合成情况，并通过流式细胞术和逆转录-聚合酶链反应评估膜联蛋白I的表达。
抗膜联蛋白I mAb逆转了地塞米松对AIA临床特征的影响，并且在没有外源性糖皮质激素的情况下加重了AIA。抗膜联蛋白I mAb导致的AIA临床加重伴随着滑膜TNFα和PGE2显著增加，提示膜联蛋白I持续抑制这些介质的产生。抗膜联蛋白I mAb治疗与白细胞细胞内膜联蛋白I显著减少相关，尽管膜联蛋白I信使核糖核酸表达增加，这与细胞外mAb通过细胞表面的消耗作用一致。
膜联蛋白I是关节炎的关键内源性抑制介质，其作用机制包括抑制细胞因子和效应分子的产生。此外，细胞外抗体对细胞内膜联蛋白I的非合成依赖性消耗支持了膜联蛋白I外化参与其作用方式的假说。
