Microarray analysis identifies a set of CXCR3 and CCR2 ligand chemokines as early IFNbeta-responsive genes in peripheral blood lymphocytes in vitro: an implication for IFNbeta-related adverse effects in multiple sclerosis.
BACKGROUND
A substantial proportion of multiple sclerosis (MS) patients discontinue interferon-beta (IFNbeta) treatment due to various adverse effects, most of which emerge at the early phase after initiation of the treatment and then diminish with time. At present, the molecular mechanism underlying IFNbeta-related adverse effects remains largely unknown. The aim of this study is to identify a comprehensive list of early IFNbeta-responsive genes (IRGs) in peripheral blood mononuclear cells (PBMC) that may play a key role in induction of adverse effects.


METHODS
Total RNA of PBMC exposed to 50 ng/ml recombinant human IFNbeta for 3 to 24 hours in vitro was processed for cDNA microarray analysis, followed by quantitative real-time RT-PCR analysis.


RESULTS
Among 1,258 genes on the array, IFNbeta elevated the expression of 107 and 87 genes, while it reduced the expression of 22 and 23 genes at 3 and 24 hours, respectively. Upregulated IRGs were categorized into conventional IFN-response markers, components of IFN-signaling pathways, chemokines, cytokines, growth factors, and their receptors, regulators of apoptosis, DNA damage, and cell cycle, heat shock proteins, and costimulatory and adhesion molecules. IFNbeta markedly upregulated CXCR3 ligand chemokines (SCYB11, SCYB10 and SCYB9) chiefly active on effector T helper type 1 (Th1) T cells, and CCR2 ligand chemokines (SCYA8 and SCYA2) effective on monocytes, whereas it downregulated CXCR2 ligand chemokines (SCYB2, SCYB1 and IL8) primarily active on neutrophils.


CONCLUSIONS
IFNbeta immediately induces a burst of gene expression of proinflammatory chemokines in vitro that have potential relevance to IFNbeta-related early adverse effects in MS patients in vivo.
Satoh
Jun-ichi
J
Department of Bioinformatics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. satoj@ncnp.go.jp
Nanri
Yusuke
Y
Tabunoki
Hiroko
H
Yamamura
Takashi
T
D003199:Computer Systems; D005796:Genes / Q000187:drug effects*; D017781:Genes, Immediate-Early; D006801:Humans; D007370:Interferon Type I / Q000009:adverse effects; D016899:Interferon-beta / Q000494:pharmacology*; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000097:blood / Q000235:genetics*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
C515334:CCR2 protein, human; C515187:CXCR3 protein, human; D007370:Interferon Type I; D008024:Ligands; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D016899:Interferon-beta