Premium
CD40 engagement on dendritic cells induces cyclooxygenase‐2 and EP2 receptor via p38 and ERK MAPKs
Author(s) -
Harizi Hedi,
Limem Ilef,
Gualde Norbert
Publication year - 2011
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2010.94
Subject(s) - prostaglandin e2 receptor , cd40 , mapk/erk pathway , microbiology and biotechnology , receptor , chemistry , signal transduction , downregulation and upregulation , biology , agonist , biochemistry , in vitro , cytotoxic t cell , gene
We have previously reported that cyclooxygenase (COX)‐2‐derived prostaglandin (PG)E2 critically regulates dendritic cell (DC) inflammatory phenotype and function through EP2/EP4 receptor subtypes. As genes activated by CD40 engagement are directly relevant to inflammation, we examined the effects of CD40 activation on inflammatory PGs in murine bone marrow‐derived DC (mBM‐DC). We showed for the first time that activation of mBM‐DC with agonist anti‐CD40 monoclonal antibody (anti‐CD40 mAb) dose dependently induces the synthesis of significant amounts of PGE2 via inducible expression of COX‐2 enzyme, as NS‐398, a COX‐2‐selective inhibitor reduces this upregulation. In contrast to lipopolysaccharide, which upregulates mBM‐DC surface levels of EP2 and EP4 receptors, CD40 crosslinking on mBM‐DC increases EP2, but not EP4, receptor expression. Flow cytometry analysis and radioligand‐binding assay showed that EP2 was the major EP receptor subtype, which binds to PGE2 at the surface of anti‐CD40‐activated mBM‐DC. Upregulation of COX‐2 and EP2 levels by CD40 engagement was accompanied by dose‐dependent phosphorylation of p38 and ERK1/2 mitogen‐activated protein kinase (MAPK) and was abrogated by inhibitors of both pathways. Collectively, we demonstrated that CD40 engagement on mBM‐DC upregulates COX‐2 and EP2 receptor expression through activation of p38 and ERK1/2 MAPK signaling. Triggering the PGE2/EP2 pathway by anti‐CD40 mAb resulted on the induction of Th2 immune response. Thus, CD40‐induced production of PGE2 by mBM‐DC could represent a negative feedback mechanism involving EP2 receptor and limiting the propagation of Th1 responses. Blocking CD40 pathway may represent a novel therapeutic pathway of inhibiting COX‐2‐derived prostanoids in chronically inflamed tissues (that is, arthritis).