Abstract
Neuroinflammation contributes to the pathogenesis of several neurological disorders and pericytes are implicated in brain inflammatory processes. Cellular inflammatory responses are orchestrated by transcription factors but information on transcriptional control in pericytes is lacking. Because the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) is induced in a number of inflammatory brain disorders, we sought to investigate its role in regulating pericyte immune responses. Our results reveal that C/EBPδ is induced in a concentration- and time-dependent fashion in human brain pericytes by interleukin-1β (IL-1β). To investigate the function of the induced C/EBPδ in pericytes we used siRNA to knockdown IL-1β-induced C/EBPδ expression. C/EBPδ knockdown enhanced IL-1β-induced production of intracellular adhesion molecule-1 (ICAM-1), interleukin-8, monocyte chemoattractant protein-1 (MCP-1) and IL-1β, whilst attenuating cyclooxygenase-2 and superoxide dismutase-2 gene expression. Altered ICAM-1 and MCP-1 protein expression were confirmed by cytometric bead array and immunocytochemistry. Our results show that knock-down of C/EBPδ expression in pericytes following immune stimulation increased chemokine and adhesion molecule expression, thus modifying the human brain pericyte inflammatory response. The induction of C/EBPδ following immune stimulation may act to limit infiltration of peripheral immune cells, thereby preventing further inflammatory responses in the brain.
Highlights
Immunocytochemical analysis of early passage cell cultures obtained from human middle temporal gyrus tissue reveals a mixed population of astrocytes, microglia and pericytes as described previously[10]
C/EBPδ was found to be induced in human brain pericyte cultures by the pro-inflammatory cytokine IL-1β
Using C/EBPδ specific siRNA we were able to attenuate the induction of pericyte C/EBPδ following immune challenge in order to identify its contribution to the inflammatory response
Summary
A role in mediating pro-inflammatory gene expression has recently been observed with several members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors, with C/EBPα 23, C/EBPβ 24 and C/EBPδ 25,26. Studies utilising rodent glia have suggested C/EBPδ has a pro-inflammatory role in the brain through enhancement of inflammatory gene transcription[25,26] This has been seen in other tissues, including the liver and lung where attenuation of C/EBPδ expression dampened inflammatory responses[30,31,32]. Induction of a closely related family member C/EBPβ has both anti-inflammatory[24] and pro-inflammatory roles in the brain[35] As such, it appears C/ EBP family members including C/EBPδ act in a cell and context dependant manner allowing it to differentially respond to the cell’s situation. We sought to investigate the function of C/EBPδ in human brain pericyte mediated inflammatory responses
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