| BackgroundMultiple sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system (CNS). The disease usually occurs in young and middle-aged adults, leading to severe disabilities. Therefore, it is of great clinical significance to elucidate the pathogenesis and develop new therapies. Among all, the theory of IL-12/IFN-γpathway, based on Th1/Th2 imbalance, is universally accepted. The theory assumes that Type 1 T Helper Cells (Th1) and interleukin-12(IL-12) play a central role in the pathogenesis of MS. However, the IL-12/IFN-γpathway theory alone can't explain all features of the disease. The IL-23/IL-17 inflammatory axis is a newly initiated pathogenesis mechanism of MS, and it proposes that interleukin-23(IL-23) induces the differentiation of Th0 cells to highly inflammatory helper T cell subtypes ( designated Th17/ThIL-17 cells) that produce interleukin-17(IL-17) which is a kind of highly inflammatory cytokines, thus lead to EAE or MS. Studies have demonstrated that potassium channel blockers (PCB) can affect the activity of inflammatory cells, thus mediate the inflammatory reaction. High-dose glucocorticosteroid is a mainstay treatment in relapses of MS. Evidence accumulates that methylprednisolone(MP)can improve the symptoms in both experimental autoimmune encephalomyelitis (EAE) and MS. However, the mechanism involved in these effects of MP is still under debate.ObjectiveThis study aimed to investigate whether or not the IL-23/IL-17 axis was involved in pathogenesis of EAE, and find out whether PCB and MP exerted anti-inflammatory effects on EAE by influencing the IL-23/IL-17 axis, thus to provide a new evidence for MP therapy in MS.MethodEAE was induced by a single 400-μl subcutaneous injection of the following emulsions in the footpad: guinea pig spinal cord homogenate (GPSCH) (50% w/v in saline), emulsified in an equal volume of Freund's complete adjuvant (FCA) to which 4 mg BCG per ml of FCA was added, and 0.1 ml of Bordetella pertussis in the instep (approximately 4.0×109 live bacteria). In the first part of this study, the rats were treated with 4-aminopyridine(4-AP), a potassium channel blocker, and the 4-AP was replaced with 2 ml NS daily in the control and EAE groups. Neurological deficit score was used to evaluate EAE. Levels of IL-23P19, IL-12P40, IL-12P35, and Cytotoxic T lymphocyte-associated antigen 8(CTLA-8) mRNA in brain tissue were detected by RT-PCR. The IL-17 level in the brain tissue supernatant was measured by the ELISA method. In the second part, rats were treated with MP, also with 2 ml NS daily in the control and EAE groups. Levels of IL-23P19, IL-12P40, IL-12P35, and Cytotoxic T lymphocyte-associated antigen 8(CTLA-8) mRNA in brain tissue were detected by RT-PCR.Results1,IL-23P19, IL-12P40, IL-12P35 and CTLA-8 mRNA levels and IL-17 protein levels in brain tissue were significantly increased in EAE rats than those in control rats (P<0.05).2,The neurological deficit score in 4-AP-treated EAE rats was significantly lower than that in EAE rats (P < 0.05).3,IL-23P19, IL-12P40, IL-12P35 and CTLA-8 mRNA levels and IL-17 protein levels in brain tissue were significantly decreased in 4-AP treated EAE rats than those in EAE rats (P<0.05).4,The levels of IL-23P19, IL-12P40, IL-12P35 and CTLA-8 mRNA and IL-17 protein in brain tissue were significantly decreased in MP treated EAE rats than those in EAE rats (P<0.05).Conclusions1,IL-23/IL-17 axis is involved in the pathogenesis of EAE.2,Potassium channel blocker 4-AP can improve the clinical symptom of EAE rats, furthermore exert anti-inflammatory effects through the intervening the IL-23/IL-17 axis.3,MP also exert anti-inflammatory effects through influencing the IL-23/IL-17 axis. |
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