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Published Online: 7 July 2004

IFN-β1b Induces Kynurenine Pathway Metabolism in Human Macrophages: Potential Implications for Multiple Sclerosis Treatment

Publication: Journal of Interferon & Cytokine Research
Volume 21, Issue Number 12

Abstract

Interferon-β1b (IFN-β1b) has limited efficacy in the treatment of relapsing-remitting multiple sclerosis (RRMS). The kynurenine pathway (KP) is chiefly activated by IFN-γ and IFN-α, leading to the production of a variety of neurotoxins. We sought to determine whether IFN-β1b induces the KP in human monocyte-derived macrophages, as one explanation for its limited efficacy. Serial dilutions of IFN-β1b (at concentrations comparable to those found in the sera of IFN-β1b-treated patients) were added to human macrophage cultures. Supernatants were collected at various time points and assayed for the KP end product, quinolinic acid (QUIN). The effect of IFN-β1b on the KP enzymes indoleamine 2,3-dioxygenase (IDO), 3-hydroxyanthranilate dioxygenase (3HAO), and quinolinate phosphoribosyltransferase (QPRTase) mRNA expression was assessed by semiquantitative RT-PCR. IFN-β1b (≥10 IU/ml) led to increased mRNA expression of both IDO and QUIN production (7901 ± 715 nM) after 72 h at 50 IU/ml IFN-β1b (p < 0.0001). This study demonstrates that IFN-β1b, in pharmacologically relevant concentrations, induces KP metabolism in human macrophages and may be a limiting factor in its efficacy in the treatment of MS. Inhibitors of the KP may be able to augment the efficacy of IFN-β in MS.

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cover image Journal of Interferon & Cytokine Research
Journal of Interferon & Cytokine Research
Volume 21Issue Number 12December 2001
Pages: 1097 - 1101
PubMed: 11798468

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Published online: 7 July 2004
Published in print: December 2001

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Gilles J. Guillemin
Centre for Immunology, St Vincent's Hospital, Sydney, Australia
Stephen J. Kerr
Centre for Immunology, St Vincent's Hospital, Sydney, Australia
Louise A. Pemberton
Centre for Immunology, St Vincent's Hospital, Sydney, Australia
Danielle G. Smith
Centre for Immunology, St Vincent's Hospital, Sydney, Australia
Georges A. Smythe
The Ray Williams Biomedical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia
Patricia J. Armati
Neuroscience Unit, School of Biological Sciences, University of Sydney, Australia
Bruce J. Brew
Centre for Immunology and Department of Neurology and HIV Medicine, St Vincent's Hospital, Sydney, Australia

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