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

Abstract

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.

Thioredoxin 1 downregulates MCP-1 secretion and expression in human endothelial cells by suppressing nuclear translocation of activator protein 1 and redox factor-1

“…A previous study showed that gene expression of MCP-1 was controlled in a stimulus-specific manner and involved differential activation of the redox-responsive transcription factors AP-1 and nuclear factor (NF)-B (64). In this study, oxLDL was used to stimulate the endothelial-like EA.hy 926 cells as a cell model of atherogenesis because oxLDL is a key pathogenic mediator of atherogenesis.…”

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

“…While further studies are warranted to identify the molecules that are responsible for the chemo-attraction of DCs, this characteristic makes DCs attractive vehicles for delivery of therapeutic molecules to infiltrative elements of gliomas. We hypothesize that glioma-derived chemokines such as RANTES 46,47 and MCP-1 48 play major roles in attracting immature DCs because immature DCs express corresponding receptors for these chemokines such as CCR1. 49 As to the maturation stage of DCs, we used relatively immature DCs that were derived from BM and cultured in the presence of GM-CSF and IL-4 for 7 days, since immature DCs are believed to be efficient in taking up foreign antigens by phagocytosis.…”

Cytokine Concentrations in the Cerebrospinal Fluid of Great Danes with Cervical Spondylomyelopathy

“…A potential explanation for the lower MCP‐1/CCL2 concentrations in GDs with more severe compression could be an exhausted MCP‐1/CCL2 response. During central nervous system inflammation, MCP‐1/CCL2 expression can be transitory 21. In vitro studies have shown that after transcription of MCP‐1/CCL2, a refractory state can ensue, during which no additional MCP‐1/CCL2 can be expressed 21.…”

“…During central nervous system inflammation, MCP‐1/CCL2 expression can be transitory 21. In vitro studies have shown that after transcription of MCP‐1/CCL2, a refractory state can ensue, during which no additional MCP‐1/CCL2 can be expressed 21. Lower MCP‐1/CCL2 concentration in CSM‐affected GDs might represent an exhausted response of this cytokine caused by the presence of long‐standing inflammation and chronic stimulation of MCP‐1/CCL2.…”