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IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis
G J Guillemin1, S J Kerr, L A Pemberton
1Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsev.edu.au
Abstract:
Interferon-beta(1b) (IFN-beta(1b)) has limited efficacy in the treatment of relapsing-remitting multiple sclerosis (RRMS). The kynurenine pathway (KP) is chiefly activated by IFN-gamma and IFN-alpha, leading to the production of a variety of neurotoxins. We sought to determine whether IFN-beta(1b) induces the KP in human monocyte-derived macrophages, as one explanation for its limited efficacy. Serial dilutions of IFN-beta(1b) (at concentrations comparable to those found in the sera of IFN-beta(1b)-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-beta(1b) 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-beta(1b) (> or =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-beta(1b) (p < 0.0001). This study demonstrates that IFN-beta(1b), 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-beta in MS.
Insights
Interferon-beta(1b) activates the kynurenine pathway (KP) in human macrophages, producing neurotoxins. This may explain its limited efficacy in treating relapsing-remitting multiple sclerosis (RRMS).
Area of Science:
- Neuroimmunology
- Biochemistry
Background:
- Interferon-beta(1b) (IFN-beta(1b)) shows limited efficacy in treating relapsing-remitting multiple sclerosis (RRMS).
- The kynurenine pathway (KP) is activated by interferons, producing neurotoxic metabolites.
Purpose of the Study:
- To investigate if IFN-beta(1b) induces KP activation in human macrophages.
- To explore a potential reason for IFN-beta(1b)'s limited therapeutic effect in MS.
Main Methods:
- Human monocyte-derived macrophages were treated with serial dilutions of IFN-beta(1b).
- Kynurenine pathway (KP) end product quinolinic acid (QUIN) was measured in supernatants.
- mRNA expression of KP enzymes (IDO, 3HAO, QPRTase) was assessed using RT-PCR.
Main Results:
- IFN-beta(1b) at pharmacologically relevant concentrations (≥10 IU/ml) increased mRNA expression of indoleamine 2,3-dioxygenase (IDO).
- Significant QUIN production was observed at 50 IU/ml IFN-beta(1b) after 72 hours (p < 0.0001).
Conclusions:
- IFN-beta(1b) induces kynurenine pathway (KP) metabolism in human macrophages.
- KP activation by IFN-beta(1b) may limit its efficacy in treating multiple sclerosis (MS).
- Inhibitors of the KP could potentially enhance IFN-beta treatment outcomes in MS.