Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs).

Abstract

Microbial infection triggers the endogenous production of immunosuppressive glucocorticoid (GC) hormones and simultaneously activates innate immunity through toll-like receptors (TLRs). How innate immune cells integrate these 2 opposing signals in dictating immunity or tolerance to infection is not known. In this study, we show that human plasmacytoid predendritic cells (pDCs) were highly sensitive to GC-induced apoptosis. Strikingly, they were protected by microbial stimulation through TLR-7 and TLR-9, but not by microbial-independent stimuli, such as interleukin-3, granulocyte macrophage colony-stimulating factor, or CD40-ligand. This protection was dependent on TLR-induced autocrine tumor necrosis factor-α and interferon-α, which collectively increased the expression ratio between antiapoptotic genes (Bcl-2, Bcl-xL, BIRC3, CFLAR) versus proapoptotic genes (Caspase-8, BID, BAD, BAX). In particular, virus-induced Bcl-2 up-regulation was dependent on autocrine interferon-α. Using small interfering RNA technology, we demonstrated that Bcl-2 and CFLAR/c-flip were essential for TLR-induced protection of pDCs from GC-induced caspase-8-mediated apoptosis. Our results demonstrate a novel property of the TLR pathway in regulating the interface between GC and innate immunity and reveal a previously undescribed mechanism of GC resistance.

• Authors: Yves Lepelletier, Raphaël Zollinger, Cristina Ghirelli, Françoise Raynaud, Réda Hadj-Slimane, Antonio Cappuccio, Olivier Hermine, Yong-Jun Liu, Vassili Soumelis
• Journal: Blood (Blood) Vol. 116 Issue 18 Pg. 3389-97 (Nov 04 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20592251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Glucocorticoids
• Interferon-alpha
• Proto-Oncogene Proteins c-bcl-2
• Toll-Like Receptor 7
• Toll-Like Receptor 9
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha

Topics

• Apoptosis
• CASP8 and FADD-Like Apoptosis Regulating Protein (immunology)
• Cells, Cultured
• Dendritic Cells (cytology, immunology, microbiology)
• Glucocorticoids (immunology)
• Humans
• Interferon-alpha (immunology)
• Proto-Oncogene Proteins c-bcl-2 (immunology)
• Toll-Like Receptor 7 (immunology)
• Toll-Like Receptor 9 (immunology)
• Toll-Like Receptors (immunology)
• Tumor Necrosis Factor-alpha (immunology)