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JNK inhibition by glucocorticoids prevents the maturation of dendritic cells induced by Toll‐like receptor 7 and Toll‐like receptor 8
Author(s) -
LARANGE Alexandre,
ANTONIOS Diane,
PALLARDY Marc,
KERDINEROMER Saadia
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.386
Subject(s) - tlr7 , mapk/erk pathway , cd86 , agonist , microbiology and biotechnology , toll like receptor , chemistry , stimulation , kinase , immune system , receptor , biology , immunology , innate immune system , t cell , endocrinology , biochemistry
Glucocorticoids (GC) are widely prescribed to treat inflammatory disorders, 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 dendritic cells (DC). The aim of our study was to evaluate the GC potential to regulate DC maturation induced by TLR7 or TLR8 agonists and to underline the molecular mechanism involved in this regulation. We showed that GC inhibit the maturation of human CD34‐derived DC (CD34‐DC) induced by the TLR7 agonist imiquimod and the TLR8 agonist 3M‐002. GC down‐regulate the expression of CD86, CD40, CD83, CCR7 and HLA‐DR on DC and inhibit IL‐6 and IL‐12p40 production by DC following TLR7 and TLR8 stimulation. Our results also show that GC do not affect TLR‐mediated activation of NF‐κB but control the activation of the JNK MAPK induced by TLR agonists, without affecting its upstream MAPK kinase MKK4. Concomitantly to JNK inhibition, we observed the induction of the dual‐specificity MAPK phosphatase (DUSP) MKP‐1 but not of others DUSPs. Moreover, Ro 31–8220, a pharmacological inhibitor of MKP‐1, abolished GC‐mediated inhibition of JNK phosphorylation. Our results underline that GC‐mediated inhibition of DC maturation is at least partly due to the inhibition of JNK activation and suggest the involvement of MKP‐1 in this process.