Genes differentially expressed by methylprednisolone in vivo in CD4 T lymphocytes from multiple sclerosis patients: potential biomarkers.
Intravenous methylprednisolone (IVMP) is the gold standard treatment in acute relapses of multiple sclerosis. Knowing the response to IVMP in advance could facilitate earlier selection of patients for subsequent courses of therapy. However, molecular mechanisms and changes in gene expression induced by methylprednisolone remain unknown. The aim of the study was to identify in vivo differentially expressed genes in relapsing-remitting multiple sclerosis patients after 3-6 days of treatment with IVMP. For this purpose, whole-genome transcription profiling of CD4+ T lymphocytes was performed before and after treatment with IVMP in 8 relapsing-remitting multiple sclerosis patients during relapse using Human GE 4x44K v2 microarrays. Differentially expressed genes were identified using a paired t test on GeneSpring v13.0 software. A P-value <0.001 and a twofold change were considered significant. Microarray data were confirmed using real-time PCR. Microarray revealed changes in gene expression: four genes were downregulated (B3GNT3, ZNF683, IFNG and TNF) and seven upregulated (DEFA4, CTSG, DEFA8P, AZU1, MPO, ELANE and PRTN3). Pathway analysis revealed the transforming growth factor-β signaling pathway to be affected. Comparison with previously published data on in vitro methylprednisolone-regulated genes showed that SMAD7, TNF and CHI3L1 were also downregulated in vivo in relapsing-remitting multiple sclerosis patients. In summary, we performed the first in vivo transcriptome analysis in CD4+ T lymphocytes before and after the treatment with IVMP in patients with multiple sclerosis. Identification of differentially expressed genes in patients receiving IVMP could improve our understanding of the molecular mechanisms underlying the therapeutic effects of IVMP and highlight potential biomarkers of the response to IVMP.
Neurology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
C
C
De Andres
Pharmacy Department, Hospital General Universitario Gregorio Marañón, Laboratory of Pharmacogenomics, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
M I
MI
García
Neurology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
H
H
Goicoechea
Neurology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
M L
ML
Martínez-Ginés
Neurology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
J M
JM
García-Domínguez
Pharmacy Department, Hospital General Universitario Gregorio Marañón, Laboratory of Pharmacogenomics, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
M L
ML
Martín
Neurology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
F
F
Romero-Delgado
Genomics Unit, Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain.
A
A
Benguría
Pharmacy Department, Hospital General Universitario Gregorio Marañón, Laboratory of Pharmacogenomics, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
M
M
Sanjurjo
Pharmacy Department, Hospital General Universitario Gregorio Marañón, Laboratory of Pharmacogenomics, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
L A
LA
López-Fernández
D061605:Administration, Intravenous / Q000379:methods; D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; D008775:Methylprednisolone
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