J Interferon Cytokine Res 2001 Dec;21(12):1097-101
Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, Brew BJ.
Centre for Immunology, St Vincent's Hospital, Sydney, Australia.
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) (>/=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.