Mediation of enhanced transcription of the IL-10 gene in T cells, upon contact with human glioma cells, by Fas signaling through a protein kinase A-independent pathway.

Abstract

Elevated expression of IL-10 has been frequently observed in tumor tissues and tumor-infiltrating cells. We show herein that transcription of the IL-10 gene in primary peripheral T cells and T cell lines is up-regulated upon contact with glioma cells without an induction of apoptosis in those T cells. Glioma-associated IL-10 induction was suppressed by interrupting the engagement of Fas and its ligand (Fas-L) with the antagonistic Ab, ZB4, by reducing Fas-L expression of glioma cells using the Fas-L-specific ribozyme, or by preventing cell-to-cell contact in a Transwell culture setting. Cross-linking of Fas with the agonistic Ab, CH-11, triggered apoptosis and enhanced the expression of IL-10 in Jurkat cells at the transcriptional and translational levels. Inhibiting caspase activities by caspase inhibitors, Z-VAD (Z-Val-Ala-Asp(Ome)-fluoromethylketone) and Z-IETD (Z-Ile-Glu(Ome)-Thr(Ome)-Asp(Ome)-fluoromethylketone), abolished this IL-10 induction in Jurkat cells. Intracellular staining detected IL-10 proteins in Fas-cross-linked Jurkat cells and in PHA-activated T cells. However, few IL-10 proteins were detectable in Jurkat cells cocultured with glioma cells, indicating a requirement of other factors for IL-10 production. Direct activation of protein kinase A (PKA) by forskolin elevated the transcription of IL-10 in Jurkat cells. However, KT5720, a selective PKA inhibitor, reduced neither anti-Fas-triggered nor glioma-associated IL-10 expression. Phosphorylation of cAMP response element binding protein and activating transcription factor-1 in Jurkat cells was not affected by coculturing with glioma cells or by anti-Fas treatment, further suggesting a PKA-independent pathway. In summary, our results demonstrate nonlethal cross-talk between tumor and immune cells leading to IL-10 dysregulation in T cells, which might contribute to Fas-L(+) tumor-associated immunosuppression.

• Authors: Bei-Chang Yang, Heng-Kai Lin, Wei-Shio Hor, Jun-Yen Hwang, Yu-Ping Lin, Ming-Yie Liu, Ying-Jan Wang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 8 Pg. 3947-54 (Oct 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 14530312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• FASLG protein, human
• Fas Ligand Protein
• Ligands
• Membrane Glycoproteins
• fas Receptor
• Interleukin-10
• Cyclic AMP-Dependent Protein Kinases
• Caspases

Topics

• Antibodies, Blocking (pharmacology)
• Apoptosis (genetics, immunology)
• Caspases (metabolism, physiology)
• Cell Communication (genetics, immunology)
• Cell Line, Tumor
• Coculture Techniques
• Cyclic AMP-Dependent Protein Kinases (physiology)
• Enzyme Activation (immunology)
• Fas Ligand Protein
• Gene Expression Regulation, Neoplastic (immunology)
• Glioma (genetics, immunology, pathology)
• Humans
• Interleukin-10 (biosynthesis, blood, genetics)
• Intracellular Fluid (immunology, metabolism)
• Jurkat Cells
• Ligands
• Membrane Glycoproteins (antagonists & inhibitors, immunology, metabolism)
• Signal Transduction (genetics, immunology)
• T-Lymphocyte Subsets (cytology, enzymology, immunology, metabolism)
• Transcription, Genetic (immunology)
• Up-Regulation (genetics, immunology)
• fas Receptor (immunology, metabolism, physiology)