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

• Published in: Prostaglandins & other lipid mediators Vol. 95; no. 1; pp. 19 - 26
• Main Authors: Prijatelj, Matevz, Celhar, Teja, Mlinaric-Rascan, Irena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2011
• Subjects: Animals; Apoptosis; B cell receptor; Cell Line, Tumor; Cell Survival - drug effects; Dinoprostone - pharmacology; Dinoprostone - physiology; EP4 receptor; Gene Expression; Immature B cell; Interphase; Mice; Mitogen-Activated Protein Kinases - metabolism; Naphthalenes - pharmacology; NF-kappa B - metabolism; NF-κB; PGE2; Phenylbutyrates - pharmacology; Pre-B Cell Receptors - metabolism; Precursor Cells, B-Lymphoid - metabolism; Precursor Cells, B-Lymphoid - physiology; Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Immature B cell; PGE2; NF-κB; EP4 receptor; B cell receptor; Apoptosis
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2011.04.001

[Display omitted] ► 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. 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.