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-gamma 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-alpha). The clinical efficacy of interferon beta (IFN-beta) therapy in reducing exacerbations of relapsing-remitting MS has been related to antagonistic effects on various activities of IFN-gamma, including MHC-II gene induction. However, there is no model to explain such antagonistic effects of IFN-beta and IFN-gamma, and the two cytokines are also known to act synergistically against viruses and in the induction of MHC-I. We show that IFN-beta does inhibit an immediate molecular event of IFN-gamma, namely activation and DNA binding of the transcription factor Stat1. We propose a model of direct interference of the IFN-gamma and IFN-alpha,beta 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-beta shows that IFN-beta significantly reduces serum levels of IFN-gamma while increasing IL-4, strongly suggesting that IFN-beta also controls the relative activation of TH1- and TH2-type T lymphocytes.
Revel
M
M
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Chebath
J
J
Mangelus
M
M
Harroch
S
S
Moviglia
G A
GA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D001943:Breast Neoplasms; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000628:therapy*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured / Q000276:immunology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D016899:Interferon-beta; D007371:Interferon-gamma