title: Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1beta in human monocytes and multiple sclerosis.
abstract: 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.
authors.affiliation: 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. danielle.burger@hcuge.ch
authors.forename: Danielle
authors.initials: D
authors.lastname: Burger
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.forename: Karim J
authors.initials: KJ
authors.lastname: Brandt
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: Lyssia
authors.initials: L
authors.lastname: Gruaz
authors.forename: Michel
authors.initials: M
authors.lastname: Chofflon
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood / Q000187:drug effects*; D053583:Interleukin-1beta / Q000187:drug effects*; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D010455:Peptides / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D010455:Peptides; D000068717:Glatiramer Acetate