IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment

J Interferon Cytokine Res. 2001 Dec;21(12):1097-101. doi: 10.1089/107999001317205231.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Humans
  • Interferon beta-1a
  • Interferon beta-1b
  • Interferon-beta / biosynthesis
  • Interferon-beta / pharmacology*
  • Interferon-beta / therapeutic use
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / pharmacology
  • Kinetics
  • Kynurenine / metabolism*
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Models, Chemical
  • Multiple Sclerosis / drug therapy
  • Quinolinic Acid / analysis
  • RNA, Messenger / biosynthesis


  • RNA, Messenger
  • Interferon beta-1b
  • Kynurenine
  • Interferon-beta
  • Interferon-gamma
  • Quinolinic Acid
  • Interferon beta-1a