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(The FASEB Journal. 2001;15:383-392.)
© 2001 FASEB

Regulation of monocyte chemoattractant protein (MCP)-1 transcription by interferon-gamma (IFN-{gamma}) in human astrocytoma cells: postinduction refractory state of the gene, governed by its upstream elements

Z.-H. LUCY ZHOU1, YULONG HAN, TAO WEI, SUMER ARAS2, PRIYA CHATURVEDI3, SARAH TYLER4, M. R. SANDHYA RANI and RICHARD M. RANSOHOFF*5

Department of Neurosciences, The Lerner Research Institute, and
* Department of Neurology and The Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA

5Correspondence: Department of Neurosciences, Lerner Research Institute, NC30, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. E-mail: ransohr{at}ccf.org

Monocyte chemoattractant protein (MCP)-1 is expressed by astrocytes in diverse inflammatory states and is a key regulator of monocyte recruitment to the central nervous system (CNS). In the current study, we addressed mechanisms by which transcription of the human MCP-1 gene (hMCP-1) was terminated, after induction by interferon (IFN)-{gamma}. Our results demonstrated that IFN-{gamma}-induced transcription of hMCP-1 was followed by a refractory state, during which hMCP-1 was resistant to restimulation by either IFN-{gamma} or heterologous activators such as TNF-{alpha}. This refractory state affected the hMCP-1 gene selectively, as other IFN-{gamma}-inducible genes remained responsive to restimulation. The IFN-{gamma}-induced hMCP-1 refractory state was governed at the transcriptional level and was sensitive to protein synthesis inhibitors, suggesting a requirement for newly expressed components. A minimal 213 base pair hMCP-1 regulatory element directed both IFN-{gamma}-mediated transcription and the subsequent refractory state. We previously demonstrated that IFN-{gamma} treatment resulted in coordinate protein occupancy in vivo of two hMCP-1 promoter elements, a gamma-activated site (GAS) and a GC-rich element. During the refractory state, IFN-{gamma} treatment failed to induce protection of either the hMCP-1 GAS element or the GC box. These results furnish insight into the expression of hMCP-1 during CNS inflammation and provide the first delineation of an IFN-{gamma}-induced transcriptional refractory state.—Zhou, Z.-H. L., Han, Y., Wei, T., Aras, S., Chaturvedi, P., Tyler, S., Rani, M. R. S., Ransohoff, R. M. Regulation of monocyte chemoattractant protein (MCP)-1 transcription by interferon-gamma (IFN-{gamma}) in human astrocytoma cells: postinduction refractory state of the gene, governed by its upstream elements.


Key Words: chemokine • gene expression • interferons • STAT factors • Sp1 transcription factor






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Copyright © 2001 by The Federation of American Societies for Experimental Biology.