Burger Danielle, Molnarfi Nicolas, Weber Martin S, Brandt Karim J, Benkhoucha Mahdia, Gruaz Lyssia, Chofflon Michel, Zamvil Scott S, Lalive Patrice H
Division of Immunology and Allergy, Clinical Immunology Unit (Hans Wilsdorf Laboratory), Department of Internal Medicine, University Hospital and Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4355-9. doi: 10.1073/pnas.0812183106. Epub 2009 Mar 2.
Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1beta is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1beta, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1beta levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contact-activated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1beta and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPS-activated monocytes, IL-1beta and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1beta production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.
醋酸格拉替雷（GA）在多发性硬化症（MS）中的作用机制以及细胞靶点仍未完全明确。IL-1β存在于中枢神经系统浸润的巨噬细胞和小胶质细胞中，是实验性自身免疫性脑脊髓炎（EAE，MS动物模型）炎症的重要介质。IL-1β的天然抑制剂，即分泌型IL-1受体拮抗剂（sIL-1Ra）可改善EAE病程。在本研究中，我们检测了GA对IL-1系统的影响。在体内，GA治疗可提高EAE小鼠和MS患者血液中sIL-1Ra水平，而IL-1β水平仍检测不到。在体外，GA本身可诱导分离的人单核细胞中sIL-1Ra的转录和产生。此外，在T细胞接触激活的单核细胞（一种与慢性炎症相关的机制）中，GA可显著降低IL-1β的表达并增强sIL-1Ra的表达。这与GA在急性炎症条件下激活的单核细胞中的作用相反。事实上，在LPS激活的单核细胞中，GA存在时IL-1β和sIL-1Ra的产生均增加。这些结果表明，在慢性炎症条件下，GA可提高循环中sIL-1Ra水平，并通过引发偏向炎症程度较低的状态直接影响单核细胞，增加sIL-1Ra的同时减少IL-1β的产生。本研究揭示了一种可能参与GA对MS治疗作用的机制。
