Methylprednisolone inhibits IFN-gamma and IL-17 expression and production by cells infiltrating central nervous system in experimental autoimmune encephalomyelitis.
BACKGROUND
Glucocorticoids have been shown to be effective in the treatment of autoimmune diseases of the CNS such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms and the site of glucocorticoids' actions are still not completely defined. The aim of this study was to investigate the in vivo effect of the synthetic glucocorticoid methylprednisolone (MP) on the expression and production of proinflammatory cytokines interferon (IFN)-gamma and interleukin (IL)-17 by cells infiltrating CNS tissue.


METHODS
Experimental autoimmune encephalomyelitis was induced in Dark Agouti (DA) rats by immunization with rat spinal cord homogenate mixed with adjuvants. Commencing on the day when the first EAE signs appeared, DA rats were injected daily for 3 days with MP and/or RU486, an antagonist of glucocorticoid receptor. Cytokine production and gene expression in CNS-infiltrating cells and lymph node cells were measured using ELISA and real time PCR, respectively.


RESULTS
Treatment of rats with MP ameliorated EAE, and the animals recovered without relapses. Further, MP inhibited IFN-gamma and IL-17 expression and production in cells isolated from the CNS of DA rats with EAE after the last injection of MP. The observed effect of MP in vivo treatment was not mediated through depletion of CD4+ T cells among CNS infiltrating cells, or through induction of their apoptosis within the CNS. Finally, the glucocorticoid receptor-antagonist RU486 prevented the inhibitory effect of MP on IFN-gamma and IL-17 production both in vitro and in vivo, thus indicating that the observed effects of MP were mediated through glucocorticoid receptor-dependent mechanisms.


CONCLUSIONS
Taken together, these results demonstrate that amelioration of EAE by exogenous glucocorticoids might be, at least partly, ascribed to the limitation of effector cell functions in the target tissue.
Miljković
Zeljka
Z
Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. zeljka_miljkovic@yahoo.com
Momcilović
Miljana
M
Miljković
Djordje
D
Mostarica-Stojković
Marija
M
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005938:Glucocorticoids / Q000627:therapeutic use*; D006727:Hormone Antagonists / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D008775:Methylprednisolone / Q000627:therapeutic use*; D015735:Mifepristone / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D015703:Antigens, CD; D005938:Glucocorticoids; D006727:Hormone Antagonists; D020381:Interleukin-17; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D007371:Interferon-gamma; D008775:Methylprednisolone