Genomic effects of IFN-beta in multiple sclerosis patients.
The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-beta-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 micro g of IFN-beta-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-beta-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1-4 h of IFN-beta treatment. The mRNAs for several genes involved in IFN-beta signaling, such as IFN-alpha/beta receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9-27), IFN-induced transmembrane protein 2 (1-8D), beta(2)-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-beta treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.
Weinstock-Guttman
Bianca
B
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA.
Badgett
Darlene
D
Patrick
Kara
K
Hartrich
Laura
L
Santos
Roseane
R
Hall
Dennis
D
Baier
Monika
M
Feichter
Joan
J
Ramanathan
Murali
M
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000998:Antiviral Agents / Q000096:biosynthesis / Q000235:genetics; D001499:Bayes Theorem; D015415:Biomarkers / Q000032:analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data; D014644:Genetic Variation / Q000276:immunology; D006801:Humans; D007273:Injections, Intramuscular; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053613:Janus Kinase 1; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods / Q000706:statistics & numerical data; D011499:Protein Processing, Post-Translational / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000998:Antiviral Agents; D015415:Biomarkers; D016899:Interferon-beta; D053613:Janus Kinase 1; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D000099192:CD69 Antigens; C507904:JAK1 protein, human