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 (TFN-gamma) stimulates the (proinflammatory) type IT inter feron receptor and is known to exacerbate multiple sclerosis (MS), In contr ast, 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 be neficial effects might be attenuated. These studies were undertaken to test this possibility with the use of quinolinic acid (QUIN) formation as a mea sure of type II receptor activation. In normal human macrophage cultures, I FN-gamma was the most potent stimulus for QUIN formation. Generally, IFN-be ta and IFN-alpha were less potent. However, an unexpected inter-patient var iability 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 pres ent data demonstrate an inter-subject variability for QUIN production follo wing exposure to the interferons. MS patients who demonstrate a pro-inflamm atory response to IFN-beta (e.g., increased QUIN) may be less likely to ben efit from this therapy.