Abstract
Glucocorticoids (GCs) are the main treatment of relapse in multiple sclerosis (MS). Decreased sensitivity to GCs in MS patients has been associated with lack of the suppressive effect of GCs on inflammatory molecules as well as increased resistance to apoptosis. We investigated GC-sensitivity by measuring the effect of intravenous methylprednisolone (IVMP) treatment on transactivation of anti-inflammatory and apoptotic genes (GILZ, MCL-1 and NOXA respectively), in accordance to clinical outcome. Thirty nine MS patients were studied: 15 with clinically isolated syndrome (CIS), 12 with relapsing remitting (RRMS) and 12 with secondary progressive (SPMS) under relapse. Patients underwent treatment with IVMP for 5 days. Blood was drawn before IVMP treatment on day 1 and 1 h after IVMP treatment on days 1 and 5. GIlZ, MCL-1 and NOXA were determined by qPCR. The Expanded Disability Status was evaluated and patients were divided according to their clinical response to IVMP. GILZ and MCL-1 gene expression were significantly higher following first IVMP treatment in responders, compared to non-responders. Furthermore, serum basal cortisol and 1,25-OH Vitamin D levels were significantly higher in clinical-responders as compared to non-clinical responders. Our findings suggest that the differential GILZ and MCL-1 gene expression between clinical-responders and non-clinical responders may implicate the importance of GILZ and MCL-1 as possible markers for predicting glucocorticoid sensitivity and response to GC-therapy in MS patients following first IVMP injection.
Highlights
Glucocorticoids (GCs) are widely used for the treatment of inflammatory autoimmune diseases, such as multiple sclerosis (MS)
All clinically isolated syndrome (CIS) patients were treatment naïve while 4/12 RRMS patients were on immunomodulatory treatment (3 received IFNb and 1 copolymer acetate) while 3/12 secondary progressive MS (SPMS) patients were treated with IFNb
GILZ is considered as a marker of GC sensitivity in vivo[25], and it has been proposed that a GILZ based therapy could represent a way to control inflammation in S LE26
Summary
Glucocorticoids (GCs) are widely used for the treatment of inflammatory autoimmune diseases, such as multiple sclerosis (MS). Glucocorticoids regulate MS at multiple levels: they suppress secretion of inflammatory mediators, such as cytokines, by T-lymphocytes and eliminate the inflammatory T cells by inducing T-cell apoptosis. GCs mediate their effects via their intracellular glucocorticoid receptor alpha and beta isoforms (GRα and GRβ respectively), both important regulators of HPA axis negative feedback and GC sensitivity. Current evidence demonstrates that GCs mediate their anti-inflammatory and apoptotic effects in lymphocytes by indirect transrepression (GRα/NF-kB pathway) as well as by direct transactivation (GRα/GRE) mode of a ction[4,5]. Several lines of evidence support that MS patients exhibit hyperactive HPA axis, as assessed by the lack of response in the combined Dex-CRH suppression test, or by elevated basal or stimulated secretion of adrenocorticotropic hormone or c ortisol[2,6,7], suggestive of GC resistance mainly at the progressive forms of M S6,8. The assessment of the in vivo glucocorticoid sensitivity in MS using the expression of GR-target genes (GILZ, DUSP, FKBP) has revealed up-regulation of GR targeted genes in patients with mild to moderate disability, while patients with severe disability displayed gene transcription concentration lower than healthy controls[12], supporting further GC resistance in MS patients
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