Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 11; pp. 4355 - 4359
• Main Authors: Burger, Danielle, Molnarfi, Nicolas, Weber, Martin S, Brandt, Karim J, Benkhoucha, Mahdia, Gruaz, Lyssia, Chofflon, Michel, Zamvil, Scott S, Lalive, Patrice H
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 17.03.2009; National Acad Sciences
• Subjects: Acetates; Autoimmune diseases; Biological Sciences; Blood; Cytokines; Mice; Monocytes; Multiple sclerosis; Receptors; Relapsing remitting multiple sclerosis; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0812183106

Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1β 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-1β, 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-1β 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-1β 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-1β 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-1β production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.