Abstract
BackgroundA substantial proportion of multiple sclerosis (MS) patients discontinue interferon-beta (IFNβ) 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 IFNβ-related adverse effects remains largely unknown. The aim of this study is to identify a comprehensive list of early IFNβ-responsive genes (IRGs) in peripheral blood mononuclear cells (PBMC) that may play a key role in induction of adverse effects.MethodsTotal RNA of PBMC exposed to 50 ng/ml recombinant human IFNβ for 3 to 24 hours in vitro was processed for cDNA microarray analysis, followed by quantitative real-time RT-PCR analysis.ResultsAmong 1,258 genes on the array, IFNβ 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. IFNβ 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.ConclusionIFNβ immediately induces a burst of gene expression of proinflammatory chemokines in vitro that have potential relevance to IFNβ-related early adverse effects in MS patients in vivo.
Highlights
A substantial proportion of multiple sclerosis (MS) patients discontinue interferonbeta (IFNβ) treatment due to various adverse effects, most of which emerge at the early phase after initiation of the treatment and diminish with time
Microarray analysis identified immediate early IFNβresponsive genes in peripheral blood mononuclear cells (PBMC) Among 1,258 genes on the array, IFNβ treatment for 3 hours elevated the expression of 107 genes in PBMC isolated from a 46 year-old healthy man, while it reduced the expression of 22 genes
The IFNβ-responsive genes (IRGs) upregulated at both time points contained 11 in vivo IRGs reported previously by us [16], including IFIT1 (IFI56), interferon-stimulated gene 15 (ISG15) (G1P2), IFIT4 (IFI60), IFI27, G1P3 (IFI6-16), IRF7, ABCB2 (TAP1), ATF3, IFITM1 (IFI17), SULT1C1, and TNFAIP6, whose expression was elevated in T cells and non-T cells ex vivo, isolated from 13 relapsing-remitting MS (RRMS) patients during IFNβ treatment for 3 to 6 months
Summary
A substantial proportion of multiple sclerosis (MS) patients discontinue interferonbeta (IFNβ) treatment due to various adverse effects, most of which emerge at the early phase after initiation of the treatment and diminish with time. The precise mechanism underlying therapeutic effects of IFNβ on MS remains to be fully elucidated, previous studies proposed several possibilities, including the inhibition of Th1 cell development [6], induction of Th2 immune deviation [7], restoration of function of the disrupted bloodbrain barrier [8], and downregulation of IFNγ-induced expression of class II major histocompatibility complex (MHC) molecules [9]. The molecular mechanisms accounting for IFNβ-related adverse effects remain unknown, most of these emerge at the early phase after initiation of the treatment, and diminish with time [12]. No biologically relevant markers capable of predicting either therapeutic or detrimental responses of IFNβ in MS are available [13]
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