Antagonism of interferon beta on interferon gamma: inhibition of signal transduction in vitro and reduction of serum levels in multiple sclerosis patients

Interferon gamma (IFN-γ acts as a mediator of multiple sclerosis (MS) exacerbations through a number of biological effects, such as induction of major histocompatibility class II complexes (MHC-II), macrophage activation and potentiation of tumor necrosis factor (TNF-α). The clinical efficacy of interferon beta (IFN-β) therapy in reducing exacerbations of relapsing–remitting MS has been related to antagonistic effects on various activities of IFN-y, including MHC-II gene induction. However, there is no model to explain such antagonistic effects of IFN-β and IFN-y, and the two cytokines are also known to act synergistically against viruses and in the induction of MHC-I. We show that IFN-β does inhibit an immediate molecular event of IFN-y, namely activation and DNA binding of the transcription factor Stat I. We propose a model of direct interference of the IFN-y and IFN-a,β signal transduction pathways accounting for antagonistic effects on some genes, which in turn activate MHC-II transcription, as well as for synergistic effects on other genes. In addition, study of MS patients treated with natural IFN-β shows that IFN-β significantly reduces serum levels of IFN-y while increasing IL-4, strongly suggesting that IFN-β also controls the relative activation of THI- and TH2-type T lymphocytes.