Interferon response heterogeneity: activation of a pro-inflammatory response by interferon alpha and beta. A possible basis for diverse responses to interferon beta in MS.
Interferon gamma (IFN-gamma) stimulates the (pro-inflammatory) type II interferon receptor and is known to exacerbate multiple sclerosis (MS). In contrast, IFN-alpha and IFN-beta are ligands for the (anti-inflammatory) type I interferon receptor and are beneficial in some (but not all) patients with MS. Should IFN-beta elicit a type-II-like pro-inflammatory response, the beneficial effects might be attenuated. These studies were undertaken to test this possibility with the use of quinolinic acid (QUIN) formation as a measure of type II receptor activation. In normal human macrophage cultures, IFN-gamma was the most potent stimulus for QUIN formation. Generally, IFN-beta and IFN-alpha were less potent. However, an unexpected inter-patient variability was observed. In some subjects, IFN-alpha was more potent than IFN-beta. In other subjects, IFN-beta was more potent than IFN-alpha. The present data demonstrate an inter-subject variability for QUIN production following exposure to the interferons. MS patients who demonstrate a pro-inflammatory response to IFN-beta (e.g., increased QUIN) may be less likely to benefit from this therapy.
Jansen
M
M
Department of Molecular Pharmacology, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina, USA.
Reinhard
J F
JF
D000328:Adult; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology*; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages; D008297:Male; D009000:Monocytes; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology
D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma