title: Effect of interferon-β1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients.
abstract: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease triggered by infiltration of activated T cells into the central nervous system. Interferon (IFN)-β is an established, safe and effective treatment for patients with relapsing-remitting MS (RRMS). The cytokine can inhibit leucocyte infiltration into the central nervous system; however, little is known about the precise molecular mechanisms. Previously, in vitro application of IFN-β1b was shown to reduce CXCL12/CXCR4-mediated monocyte migration. Here, we analysed the effects of IFN-β1b on CXCR4-dependent T cell function. In vitro exposure to IFN-β1b (1000 U/ml) for 20 h reduced CXCR4-dependent chemotaxis of primary human T cells from healthy individuals and patients with RRMS. Investigating the IFN-β1b/CXCR4 signalling pathways, we found no difference in phosphorylation of ZAP70, ERK1/2 and AKT despite an early induction of the negative regulator of G-protein signalling, RGS1 by IFN-β1b. However, CXCR4 surface expression was reduced. Quantitative real time-PCR revealed a similar reduction in CXCR4-mRNA, and the requirement of several hours' exposure to IFN-β1b supports a transcriptional regulation. Interestingly, T cells from MS patients showed a lower CXCR4 expression than T cells from healthy controls, which was not reduced further in patients under IFN-β1b therapy. Furthermore, we observed no change in CXCL12-dependent chemotaxis in RRMS patients. Our results demonstrate clearly that IFN-β1b can impair the functional response to CXCR4 by down-regulating its expression, but also points to the complex in vivo effects of IFN-β1b therapy.
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wostradowski
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Gudi
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Pul
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gingele
authors.affiliation: Department of Nephrology, Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.|Institute for Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Lindquist
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stangel
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.|Department of Neurochemistry and Molecular Biology, Leibniz-Institute for Neurobiology, and Neurological Rehabilitation Centre, MEDIAN Kliniken, Magdeburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000068576:Interferon beta-1b / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D000068576:Interferon beta-1b
keywords: CXCL12; CXCR4 expression; interferon-β1b; migration; primary human T cells