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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
Published on: August 13, 2013
Abrogation of TLR4 and CD14 expression and signaling in human adrenocortical tumors
Waldemar Kanczkowski1, Piotr Tymoszuk, Monika Ehrhart-Bornstein
1Department of Medicine III, Technical University of Dresden, Dresden, Germany.
Context:
Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis. The expression of innate immunity receptor Toll-like receptor 4 (TLR4) was recently reported in various human tumors, and TLR4 was shown to regulate tumor immune escape processes, proliferation, and resistance to chemotherapeutical agents.
Objective:
The aim of this study was to investigate TLR4 expression, signaling, and function in the process of tumorigenesis in the human adrenal cortex.
Measurements And Main Results:
Real-time PCR analysis of human ACC (n=8), adenoma (n=8), and ACC cell lines (SW13, NCI-H295R, and HAC15) revealed a significant down-regulation of TLR4, MD2 (myeloid differentiation protein-2), and cluster of differentiation 14 (CD14) mRNA compared with normal human adrenal cortex and adrenocortical cells in primary culture. Furthermore, immunohistochemistry revealed an abrogation of TLR4 and CD14 expression in ACC but not adenoma tissues. Western blot analysis of MAPK, AKT, activator protein-1, and nuclear factor-κB signaling revealed that the ACC cell lines are unresponsive to lipopolysaccharide action. Restoration of TLR4 signaling by stable transfection of TLR4-CD14 plasmid into NCI-H295R cells sensitized them to lipopolysaccharide incubation as shown by nuclear factor-κB activation and decreased cell viability and induced apoptosis in these cells.
Conclusion:
Our results demonstrate a significant reduction in the expression of TLR4 and CD14 and an inactivation of TLR4 signaling in ACCs. Furthermore, our data show that reintroduction of TLR4 expression in ACCs may provide a novel therapeutic strategy for adrenal cancer.
Insights
Toll-like receptor 4 (TLR4) is downregulated in adrenocortical carcinoma (ACC), impairing immune response. Restoring TLR4 expression in ACC may offer a new therapeutic strategy for adrenal cancer.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with a poor prognosis.
- Toll-like receptor 4 (TLR4), an innate immunity receptor, is implicated in tumor immune escape, proliferation, and chemoresistance.
Purpose of the Study:
- To investigate the expression, signaling, and function of TLR4 in human adrenal cortex tumorigenesis.
- To understand the role of TLR4 in adrenocortical carcinoma development.
Main Methods:
- Real-time PCR and immunohistochemistry to assess TLR4, MD2, and CD14 expression in ACC, adenoma, and normal adrenal tissues.
- Western blot analysis to evaluate MAPK, AKT, AP-1, and NF-κB signaling pathways.
- Functional studies involving restoration of TLR4 signaling in ACC cell lines.
Main Results:
- Significant downregulation of TLR4, MD2, and CD14 mRNA and protein expression was observed in ACC compared to normal adrenal cortex.
- ACC cell lines exhibited unresponsiveness to lipopolysaccharide (LPS) due to inactivated TLR4 signaling.
- Restoration of TLR4 signaling in ACC cells sensitized them to LPS, inducing apoptosis and decreasing viability.
Conclusions:
- ACCs show reduced TLR4/CD14 expression and inactivated TLR4 signaling.
- Reintroducing TLR4 expression presents a potential novel therapeutic strategy for adrenocortical carcinoma.
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