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Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia
C M McManus1, C F Brosnan, J W Berman
1Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Abstract:
Leukocyte infiltration into the central nervous system (CNS) is a key event in the inflammatory processes of neuroimmunologic diseases. Microglia, resident macrophages of the CNS, may contribute to this process by elaborating chemoattractants that are capable of recruiting leukocytes across the blood-brain barrier. Such factors have been detected in the CNS of animal models of multiple sclerosis and in the brains of human and nonhuman primates with AIDS encephalitis. As the expression of these chemoattractants may play an important role in the initiation and progression of neuroimmunologic diseases, we analyzed expression of the chemokines MIP-1 alpha, MIP-1 beta, MCP-1, and RANTES in human fetal microglial cultures. Unstimulated microglia expressed minimal levels of MIP-1 alpha, MIP-1 beta, and MCP-1, while RANTES was undetectable. In response to LPS, TNF-alpha, or IL-1 beta, both MIP-1 alpha and MIP-1 beta were induced at the mRNA and protein levels in a dose- and time-dependent manner. IFN-gamma did not significantly induce chemokine expression. MCP-1 was detectable in LPS- and cytokine-treated microglia. TGF-beta, a cytokine with down-modulatory effects on other cell types, had little effect on chemokine expression in microglia when used concomitantly before or during treatment with LPS. These results illustrate the ability of certain inflammatory stimuli to induce expression of MIP-1 alpha, MIP-1 beta, and MCP-1 by human fetal microglia. The expression of these chemoattractants may function to recruit inflammatory cells into the CNS during the course of neuroimmunologic diseases and may modulate the ability of HIV to infect the CNS.
Insights
Human fetal microglia release chemokines like MIP-1 alpha, MIP-1 beta, and MCP-1 when exposed to inflammatory signals. This chemokine release may recruit immune cells to the central nervous system (CNS) in neuroimmunologic diseases.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Leukocyte infiltration into the central nervous system (CNS) is critical in neuroimmunologic diseases.
- Microglia, the resident immune cells of the CNS, may drive this infiltration by releasing chemoattractants.
- These chemoattractants have been observed in conditions like multiple sclerosis and AIDS encephalitis.
Purpose of the Study:
- To analyze the expression of specific chemokines (MIP-1 alpha, MIP-1 beta, MCP-1, RANTES) in human fetal microglial cultures.
- To understand how inflammatory stimuli influence chemokine production by microglia.
- To assess the potential role of microglial chemoattractants in neuroinflammation and HIV CNS infection.
Main Methods:
- Cultured human fetal microglia were stimulated with lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta).
- Chemokine expression was analyzed at both the mRNA and protein levels.
- Dose- and time-dependent effects of stimuli were evaluated.
Main Results:
- Unstimulated microglia showed minimal expression of MIP-1 alpha, MIP-1 beta, and MCP-1; RANTES was undetectable.
- LPS, TNF-alpha, and IL-1 beta significantly induced MIP-1 alpha and MIP-1 beta mRNA and protein in a dose- and time-dependent manner.
- MCP-1 was also detected upon stimulation, while IFN-gamma had minimal effect, and TGF-beta showed little impact on chemokine expression.
Conclusions:
- Certain inflammatory stimuli can induce the expression of MIP-1 alpha, MIP-1 beta, and MCP-1 in human fetal microglia.
- These induced chemoattractants may play a role in recruiting inflammatory cells to the CNS in neuroimmunologic diseases.
- Microglial chemokine production might influence HIV's ability to infect the CNS.