NMDA receptors regulate production of IL-17 and CD4 CD8 T cells in multiple sclerosis

This study was conducted to investigate in vitro the effects of non-competitive NMDA receptor antagonists (+)-MK801 on ability of peripheral CD4 and CD8 T-lymphocytes from healthy volunteers and patients with multiple sclerosis (MS) to produce IL-17 as well as on expression of a gene encoding a transcription factor RORyt. Peripheral blood mononuclear cells (PBMS) obtained from healthy donors (15) and patients suffer from multiple sclerosis (12) were incubated with phorbol-myristate-acetate (10 ng/ml) plus ionomycin (1 mg/ml) with or without (+)-MK801 (100 mM). Intracellular content of IL-17 in stimulated CD4 and CD8 lymphocytes was assayed 4 h later. Analysis of RORC mRNA level in PBMS was performed 2 h later. Blockade of NMDA receptors is not accompanied by changes in the number CD4 and CD8 cells of patients with multiple sclerosis and healthy individuals. No significant differences in ratio of CD4 /CD8 were found between MS patients and healthy subjects. Incubation of the cells with antagonist of NMDA receptors in the presence of inductors significantly reduced the amount of IL-17 - producing CD4 cells in MS patients and healthy donors. Furthermore the more pronounced effect of blockade was shown in cells derived from MS patients. Similar patterns are demonstrated for IL-17 - producing CD8 cells. In general, IL-17 - producing CD4 and CD8 lymphocytes from MS patients were more sensitive to NMDA receptor antagonist comparing to control subjects. Moreover, the effect of blockade of NMDA receptors has been more conspicuous in CD8 IL-17 cells in both groups. Subsequent experiments have shown that NMDA receptors are involved in the control of IL-17 synthesis at the level of transcriptional regulation of the gene encoding the transcription factor RORyt.

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