CD40 engagement on dendritic cells induces cyclooxygenase‐2 and EP2 receptor via p38 and ERK MAPKs

Abstract

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).

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A supercritical CO2 extract from seabuckthorn leaves inhibits pro-inflammatory mediators via inhibition of mitogen activated protein kinase p38 and transcription factor nuclear factor-κB

“…Genes activated by CD40 engagement are directly relevant to inflammation. In a recent study, Harizi et al [39] showed that CD40 engagement on dendritic cells induces COX-2 via p38 and ERK MAPKs. COX-2 is highly expressed in macrophages of inflamed tissues, which can be activated via CD40 to produce tissue factor [41], thereby enhancing the chronic inflammation.…”

“…CD40 is a cell membrane-spanning protein of 50 kDa which is expressed on B lymphocytes, macrophages, dendritic cells and fibroblasts [39,40]. Genes activated by CD40 engagement are directly relevant to inflammation.…”