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

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-I. 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.