Modulation of astrocyte inducible nitric oxide synthase and cytokine expression by interferon β is associated with induction and inhibition of interferon γ‐activated sequence binding activity

• Published in: Journal of neurochemistry Vol. 83; no. 5; pp. 1120 - 1128
• Main Authors: Hua, Liwei L., Kim, Mee‐Ohk, Brosnan, Celia F., Lee, Sunhee C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2002; Blackwell
• Subjects: astrocytes; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Cells, Cultured; Cytokines - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - drug effects; Down-Regulation - physiology; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; human; Humans; Interferon-beta - pharmacology; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; interferons; Interleukin-1 - pharmacology; Interleukin-6 - genetics; Interleukin-6 - metabolism; Isolated neuron and nerve. Neuroglia; nitric oxide; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nuclease Protection Assays; Response Elements - drug effects; Response Elements - physiology; RNA, Messenger - metabolism; signal transducer and activator of transcription; STAT1 Transcription Factor; STAT2 Transcription Factor; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; tumor necrosis factor‐α; Vertebrates: nervous system and sense organs; Human; Cerebral cortex; Enzyme; Neuroglia; Cytokine; Central nervous system; Inflammation; Astrocyte; Gene expression; In vitro; signal transducer and activator of transcription; Nitric-oxide synthase; Interleukin 6; interferons; Nitric oxide; tumor necrosis factor-α; Beta interferon; Oxidoreductases; astrocytes; Tumor necrosis factor α; Brain (vertebrata); Gamma interferon
• DOI: 10.1046/j.1471-4159.2002.01226.x
• ISSN: 0022-3042

Although interferon (IFN)‐β is firmly established as a therapeutic agent for multiple sclerosis, information regarding its role in astrocyte cytokine production is limited. In primary cultures of human astrocytes, we determined the effects of IFN‐β on astrocyte cytokine [tumor necrosis factor‐alpha (TNF‐α) and interleukin (IL)‐6] and inducible nitric oxide synthase (iNOS) expression by ribonuclease protection assay and ELISA. We found that IFN‐β inhibited astrocyte cytokine/iNOS induced by IL‐1 plus IFN‐γ, but in the absence of IFN‐γ, IFN‐β enhanced IL‐1‐induced cytokine/iNOS expression. Electrophoretic mobility shift analysis (EMSA) demonstrated that IFN‐γ induced sustained IFN‐γ‐activated sequence (GAS) binding, while IFN‐β induced transient GAS binding. When used together, IFN‐β inhibited IFN‐γ‐induced GAS binding activity. Nuclear factor‐kappa B (NF‐κB) activation was not altered by either IFNs, whereas IFN stimulated response element (ISRE) was only activated by IFN‐β and not IFN‐γ. These results suggest that IFN‐β can both mimic and antagonize the effect of IFN‐γ by modulating induction of nuclear GAS binding activity. Our results demonstrating differential regulation of astrocyte cytokine/iNOS induction by IFN‐β are novel and have implications for inflammatory diseases of the human CNS.