Research Information System
FASEB Journal, vol.15, no.2, pp.383-392, 2001 (SCI-Expanded)
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)-γ. Our results demonstrated that IFN-γ-induced transcription of hMCP-1 was followed by a refractory state, during which hMCP-1 was resistant to restimulation by either IFN-γ or heterologous activators such as TNF-α. This refractory state affected the hMCP-1 gene selectively, as other IFN-γ-inducible genes remained responsive to restimulation. The IFN-γ-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-γ-mediated transcription and the subsequent refractory state. We previously demonstrated that IFN-γ 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-γ 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-γ-induced transcriptional refractory state.