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Regulation of IL-10 expression by upstream stimulating factor (USF-1) in glioma-associated microglia
Leying Zhang1, Michelle Van Handel, Jill M Schartner
1Department of Neurosurgery, Beckman Research Institute, City of Hope National Medical Center, CA 91010, USA.
Abstract:
Understanding the local CNS immune response to neoplasms is essential in the development of immune-based treatments for malignant brain tumors. Using rodent glioma models, we have recently found tumor-associated microglia/macrophages (MG/MP) to be less responsive to known MG/MP activators such as CpG, LPS and IFN-gamma. To understand the mechanism of MG/MP suppression, nuclear extracts from rodent intracranial C6 gliomas, C6 glioma-associated MG/MP, normal brain, and normal MG/MP were obtained and studied using Electrophoretic Mobility Shift Assay (EMSA). Among the nuclear factors studied (AP-1, IRF, USF-1 and Stat-1) only USF-1, which is constitutively expressed in most cells, was down-regulated in tumor-associated MG/MP, but not normal MG/MP. Because tumor-associated MG/MP had higher expression of IL-10 (but not TNF-alpha or TGF-beta), we evaluated the role of USF-1 on IL-10 expression. siRNA mediated inhibition of USF-1 expression in primary MG/MP cultures resulted in up-regulation of IL-10 mRNA but not TNF-alpha or TGF-beta. These findings suggest that USF-1 may play a role in IL-10 regulation in MG/MP in brain tumors.
Insights
Tumor-associated microglia/macrophages (MG/MP) in brain tumors show suppressed immune responses. Down-regulation of USF-1 in MG/MP may contribute to increased IL-10, impacting tumor immunity.
Area of Science:
- Neuroimmunology
- Oncology
- Molecular Biology
Background:
- Malignant brain tumors necessitate understanding CNS immune responses for effective immunotherapy.
- Tumor-associated microglia/macrophages (MG/MP) in glioma models exhibit reduced responsiveness to common immune activators.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying MG/MP suppression in the brain tumor microenvironment.
- To investigate the role of specific nuclear factors in regulating MG/MP function within gliomas.
Main Methods:
- Utilized rodent intracranial C6 glioma models.
- Analyzed nuclear extracts from tumor-associated and normal MG/MP using Electrophoretic Mobility Shift Assay (EMSA).
- Investigated IL-10 expression regulation via siRNA-mediated inhibition of USF-1 in primary MG/MP cultures.
Main Results:
- Down-regulation of the nuclear factor USF-1 was observed specifically in tumor-associated MG/MP.
- Tumor-associated MG/MP displayed higher expression of IL-10 compared to normal MG/MP.
- Inhibition of USF-1 in MG/MP cultures led to increased IL-10 mRNA expression.
Conclusions:
- USF-1 is down-regulated in MG/MP within the brain tumor microenvironment.
- USF-1 may play a critical role in the regulation of IL-10 expression in MG/MP.
- These findings offer insights into the immunosuppressive mechanisms in brain tumors and potential therapeutic targets.
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