IFN-β _1binduces kynurenine pathway metabolism in human macrophages: Potential implications for multiple sclerosis treatment

Interferon-β 1b(IFN-β 1b) 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-β 1binduces the KP in human monocyte-derived macrophages, as one explanation for its limited efficacy. Serial dilutions of IFN-β 1b(at concentrations comparable to those found in the sera of IFN-β 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-β 1bon 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-β 1b(≥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-β 1b(p < 0.0001). This study demonstrates that IFN-β 1bin 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.