Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs).
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.
Lepelletier
Yves
Y
Université Paris Descartes, Paris, France.
Zollinger
Raphaël
R
Ghirelli
Cristina
C
Raynaud
Françoise
F
Hadj-Slimane
Réda
R
Cappuccio
Antonio
A
Hermine
Olivier
O
Liu
Yong-Jun
YJ
Soumelis
Vassili
V
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D005938:Glucocorticoids / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D005938:Glucocorticoids; D016898:Interferon-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha