Glucocorticoids inhibit dendritic cell maturation induced by Toll-like receptor 7 and Toll-like receptor 8.
GCs are widely prescribed to treat inflammatory disorders and autoimmune and allergic diseases. Their anti-inflammatory and immunosuppressive effects may be related, in part, to their ability to control the maturation and functions of DCs. Here, we report that GCs inhibit the maturation of human CD34-DCs induced by the TLR7 agonist imiquimod and the TLR8 agonist 3M-002. GCs down-regulate the expression of CD86, CD40, CD83, CCR7, and HLA-DR on DCs and inhibit IL-6 and IL-12p40 production by DCs following TLR7 and TLR8 stimulation. This inhibitory effect is abolished by RU486, suggesting a role for GR transcriptional activity. Our results also show that GCs do not affect TLR-mediated DNA-binding activity of NF-κBp65. We observe that GCs control the activation of JNK induced by TLR agonists, without affecting its upstream MKK4. However, p38MAPK activation is not affected by GCs. Concomitantly to JNK inhibition, we observe the induction of the DUSP MKP-1 but not of other DUSPs by GCs. However, although silencing of MKP-1 in DCs reverses GC-mediated JNK inhibition, no significant effect on GC-induced inhibition of DC maturation was evidenced. Our results show that GCs alter DC maturation in response to TLR7 or TLR8 through a mechanism involving GR transcriptional activity.
University Paris-Sud, INSERM UMR-S 749 and INSERM UMR-S 996, and INSERM, 92296 Châtenay-Malabry, France.
Alexandre
A
Larangé
Diane
D
Antonios
Marc
M
Pallardy
Saadia
S
Kerdine-Römer
D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors / Q000502:physiology*
D005938:Glucocorticoids; D006131:Growth Inhibitors; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D003907:Dexamethasone