A cyclooxygenase-2/prostaglandin E2 pathway augments activation-induced cytosine deaminase expression within replicating human B cells

• Published in: The Journal of immunology (1950) Vol. 185; no. 9; pp. 5300 - 5314
• Main Authors: Lee, Hyunjoo, Trott, Joshua S, Haque, Shabirul, McCormick, Steven, Chiorazzi, Nicholas, Mongini, Patricia K A
• Format: Journal Article
• Language: English
• Published: United States 01.11.2010
• Subjects: B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cyclooxygenase 2 - immunology; Cyclooxygenase 2 - metabolism; Cytidine Deaminase - biosynthesis; Dinoprostone - immunology; Dinoprostone - metabolism; Humans; Immunoblotting; Lymphocyte Activation - immunology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000574

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 PGE(2) synthase-1, and the PGE(2)R, 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 PGE(2) 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 PGE(2) supplementation. This was not due to PGE(2)-promoted differentiation to plasma cells or to greater downstream switching. Rather, because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE(2)-supplemented cultures, it appears more likely that PGE(2) 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 PGE(2) feed-forward mechanism for augmenting COX-2 pathway proteins promotes progressively increased levels of AID mRNA, protein, and function.