Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β 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-1␤ 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-1␤, 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-1␤ levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contactactivated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1␤ and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPSactivated monocytes, IL-1␤ 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-1␤ production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.experimental autoimmune encephalitis ͉ cellular contact ͉ inflammation ͉ autoimmune disease

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

“…We previously demonstrated that GA increases the circulating levels of sIL-1Ra in GA-treated MS patients and EAE mice (29). This observation corroborates the triggering of sIL-1Ra production by GA in isolated blood monocytes.…”

“…PI3Ks and extracellular signal-regulated kinase-1/2 (ERK1/2) have been shown to contribute to the induction of sIL-1Ra in monocytes. To assess whether GA was able to turn on PI3K/Akt and MAPK pathways, monocytes were activated by an optimal concentration of GA (25 μg/mL) that was previously determined (29). GA induced the phosphorylation of Akt and ERK1/2, i.e., downstream elements of PI3Ks and MEK1/2, both kinases being coordinately phosphorylated, reaching a maximum at 2 h (Fig.…”

“…Moreover, contrasting with GA effects, IL-1β production is induced in monocytes upon ligation of MHC class II by antibodies, F(ab) from the latter, and superantigens (42,(44)(45)(46). As GA induces sIL-1Ra but not IL-1β production in human monocytes (29), it is unlikely that MHC class II molecules may act as GA receptors to induce sIL-1Ra production. Furthermore, the demonstration that in MHC class II-deficient mice, GA induces type II monocyte differentiation favoring the production of antiinflammatory cytokines, strongly indicates that GA may affect monocyte function in the absence of MHC class II molecules (47).…”

“…Like IFNβ, another immunomodulator used in MS therapy (27,28), GA induces sIL-1Ra production in isolated human monocytes, an activity reflected by the enhancement of sIL-1Ra levels in the blood of GA-treated MS patients and EAE mice (29). Thus, both GA and IFNβ, which display comparable therapeutic effects (30), act on sIL-1Ra levels that might be a common mode of action in MS treatment.…”

TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+Treg cells

“…For active immunization, 8-week-old mice were immunized with MOG 35-55 as described [56]. Briefly, female B6 mice deficient in TLR7 and WT were immunized with 100 μg MOG in CFA containing MT, subcutaneously on the right flank (100 μL/animal) on day 0.…”