Abstract
Interactions between immune effector cells of the central nervous system appear to directly or indirectly influence the progress/regression of multiple sclerosis (MS). Here, we report that glial STAT1 and −3 are distinctively phosphorylated following the interaction of activated lymphocytes and glia, and this effect is significantly inhibited by glatiramer acetate (GA), a disease-modifying drug for MS. GA also reduces the activations of STAT1 and −3 by MS-associated stimuli such as IFNγ or LPS in primary glia, but not neurons. Experiments in IFNγ- and IFNγ receptor-deficient mice revealed that GA-induced inhibitions of STAT signaling are independent of IFNγ and its receptor. Interestingly, GA induces the expression levels of suppressor of cytokine signaling-1 and −3, representative negative regulators of STAT signaling in glia. We further found that GA attenuates the LPS-triggered enhancement of IL-2, a highly produced cytokine in patients with active MS, in CD4+ T cells co-cultured with glia, but not in CD4+ T cells alone. Collectively, these results provide that activation of glial STATs is an essential event in the interaction between glia and T cells, which is a possible underlying mechanism of GA action in MS. These findings provide an insight for the development of targeted therapies against MS.
Highlights
Administration of GA as well as parenteral route administration is effective suppressing EAE models in rats, mice and in primates[15]
In an attempt to delineate the molecular mechanism(s) underlying Multiple sclerosis (MS), we set out to determine which inflammatory signaling molecules could be affected by an interaction between glia and activated lymphocytes, and examined the effect of GA on such signaling in central nervous system (CNS) immune effector cells
Using antibodies against representative inflammatory signaling molecules, we explored which signaling molecules could be influenced by the interaction of activated lymphocytes and glia
Summary
Administration of GA as well as parenteral route administration is effective suppressing EAE models in rats, mice and in primates[15]. Both T cell infiltrates and activated glial cells increase markedly, and elicit immunological neurodegenerative responses[1] The dysregulation of these inflammatory cells further recruits/activates T cells and innate immune cells. Our results suggest that GA efficiently modulates the activations of STAT1 and −3 in glial cells, brain-resident immune cells, and that this affects the activation of T cells and the production of inflammatory mediators. These observations improve our understanding of the molecular mechanisms underlying MS and may facilitate the development of effective targeted therapies against this disease
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