IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment.
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.
Guillemin
G J
GJ
Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsev.edu.au
Kerr
S J
SJ
Pemberton
L A
LA
Smith
D G
DG
Smythe
G A
GA
Armati
P J
PJ
Brew
B J
BJ
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D007700:Kinetics; D007737:Kynurenine / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008956:Models, Chemical; D009103:Multiple Sclerosis / Q000188:drug therapy; D017378:Quinolinic Acid / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger; D000068576:Interferon beta-1b; D007737:Kynurenine; D016899:Interferon-beta; D007371:Interferon-gamma; D017378:Quinolinic Acid; D000068556:Interferon beta-1a