IFN- β 1b Induces Kynurenine Pathway Metabolism in Human Macrophages: Potential Implications for Multiple Sclerosis Treatment

Abstract

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 _1b induces 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 _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-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 _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-β in MS.