Immunology and cell biologyAug 11, 2010

Activating CD40 on immune cells triggers inflammation-related enzymes and receptors through specific signaling pathways

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Updated Apr 5, 2026

Abstract

Activation of murine bone marrow-derived dendritic cells (mBM-DC) with anti-CD40 monoclonal antibody significantly induces the synthesis of prostaglandin E2 (PGE2) via COX-2 expression.

CD40 engagement increases COX-2 expression and PGE2 synthesis in mBM-DC in a dose-dependent manner.
Inhibition of COX-2 with NS-398 reduces the upregulation of PGE2 in anti-CD40 mAb-activated mBM-DC.
CD40 activation enhances EP2 receptor levels on mBM-DC, while EP4 receptor levels remain unchanged.
The major receptor subtype binding PGE2 on anti-CD40-activated mBM-DC is identified as EP2.
Activation of p38 and ERK1/2 MAPK signaling pathways is associated with the upregulation of COX-2 and EP2 levels following CD40 engagement.
The production of PGE2 in response to CD40 activation may serve as a negative feedback mechanism that limits Th1 immune responses.

Simplified

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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Activating CD40 on immune cells triggers inflammation-related enzymes and receptors through specific signaling pathways

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