Regulation of monocyte chemoattractant protein (MPC)-1 transcription by interferon-gamma (IFN-γ) in human astrocytoma cells: Postinduction refractory state of the gene, governed by its upstream elements
FASEB Journal, cilt.15, sa.2, ss.383-392, 2001 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 15 Sayı: 2
- Basım Tarihi: 2001
- Doi Numarası: 10.1096/fj.00-0373com
- Dergi Adı: FASEB Journal
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.383-392
- Anahtar Kelimeler: Chemokine, Gene expression, Interferons, Sp1 transcription factor, STAT factors
- Ankara Üniversitesi Adresli: Evet
Özet
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.