Prostaglandin EP4 receptor enhances BCR-induced apoptosis of immature B cells

Prostaglandin E2 (PGE2) is emerging as an important co-modulator of B cell responses. Using a pharmacological approach, we aimed to delineate the role of PGE2 in B cell receptor (BCR) induced apoptosis of immature B cells. Gene and protein expression analyses showed that, of the four PGE2 receptors subtypes, only EP4 receptor is upregulated upon BCR cross-linking, leading to sensitization of WEHI 231 cells towards PGE2 mediated inhibitory effects. EP4 receptor antagonist ONO-AE3-208, was able to completely revert the observed effects of PGE2. The engagement of EP4 receptor promotes BCR-induced G0/G1 arrest of WEHI 231 cells, resulting in enhanced caspase mediated, BCR-induced apoptosis. We addressed, mechanistically, the interplay between BCR and EP4 receptor signaling components. Prostaglandin1–alcohol (Pge1–OH), a selective EP4 receptor agonist inhibits BCR-induced activation of NF-κB by suppression of BCR-induced IκBα phosphorylation. Disruption of prosurvival pathways is a possible mechanism by which PGE2 enhances BCR-induced apoptosis in immature B lymphocytes.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► EP4 receptor expression is upregulated upon BCR receptor cross-linking. ► EP4 receptor antagonist can completely revert the inhibitory effects of PGE2. ► EP4 receptor agonist Pge1–OH and PGE2 promote BCR-induced G0/G1 arrest of WEHI 231 cells. ► B cell and EP4 receptors synergistically contribute to caspase mediated apoptosis. ► EP4 receptor inhibits BCR induced activation of NF-κB by suppression of IκBα phosphorylation.