Prostaglandin E2 upregulates p53 mRNA and protein within activated human B lymphocytes (45.17)

Abstract

Prostaglandin E2 (PGE2), a product of COX-2, plays a central role in inflammation and is elevated in pre-neoplastic tissue and malignancies, as well as in activated normal B lymphocytes. PGE2-induced signals via EP receptors modulate cAMP and/or calcium levels and can cross-talk with other signaling pathways (e.g. MAPK and NF-kB). p53 is a tumor suppressor with broad effects that include negative regulation of cell cycle, DNA repair, and induction of apoptosis. This study describes a role for PGE2 in regulating B cell p53 mRNA and protein. Purified human B2 cells from spleen/tonsil were pre-activated with stimuli resembling those found in sites of inflammation, i.e. surrogate C3dg-coated antigen + IL4 + BAFF. At d 4-5, cell density-limiting cultures were pulsed with PGE2 (50 nM) and harvested 1, 3, 8, 24, and 31 h later. p53 mRNA was monitored by both quantitative and qualitative RT-PCR. Exogenous PGE2 significantly enhanced p53 mRNA expression, in a time dependent fashion, over 3-31 h. This was accompanied by elevated mRNA for BID, a pro-apoptotic protein known to be transcriptionally regulated by p53, and linked to PGE2-elevated levels of p53 protein in replicating blasts. The above findings contrast with evidence that PGE2 promotes the expression of pro-survival Mcl-1 within replicating B cells. Taken together, they indicate that PGE2-mediated signals modulate both pro-survival and pro-apoptotic molecules in normal replicating human B lymphocytes.