A Cyclooxygenase-2/Prostaglandin E2 Pathway Augments Activation-Induced Cytosine Deaminase Expression within Replicating Human B Cells

Abstract

Within inflammatory environments, B cells encountering foreign or self-Ag can develop tertiary lymphoid tissue expressing activation-induced cytosine deaminase (AID). Recently, this DNA-modifying enzyme was detected in nonlymphoid cells within several inflamed tissues and strongly implicated in malignant transformation. This study examines whether a cyclooxygenase 2 (COX-2) pathway, often linked to inflammation, influences AID expression in activated B lymphocytes. In this paper, we report that dividing human B cells responding to surrogate C3d-coated Ag, IL-4, and BAFF express AID, as well as COX-2. A progressive increase in AID with each division was paralleled by a division-related increase in a COX-2–linked enzyme, microsomal PGE2 synthase-1, and the PGE2R, EP2. Cells with the greatest expression of AID expressed the highest levels of EP2. Although COX-2 inhibitors diminished both AID expression and IgG class switching, exogenous PGE2 and butaprost, a selective EP2 agonist, augmented AID mRNA/protein and increased the numbers of IgG+ progeny. Despite the latter, the proportion of IgG+ cells within viable progeny generally declined with PGE2 supplementation. This was not due to PGE2-promoted differentiation to plasma cells or to greater downstream switching. Rather, because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE2-supplemented cultures, it appears more likely that PGE2 facilitates AID-dependent DNA double-strand breaks that block B cell cycle progression or promote activation-induced cell death, or both. Taken together, the results suggest that a PGE2 feed-forward mechanism for augmenting COX-2 pathway proteins promotes progressively increased levels of AID mRNA, protein, and function.