EFFECTS OF B CELL COX-2/PGE2 ON ACTIVATION-INDUCED CYTOSINE DEAMINASE (AID) (35.4)

Abstract

Abstract The rate-limiting enzyme for prostaglandin E2 (PGE2) production, i.e. COX-2, was recently found to be expressed and functional within human B cells. In B2 cell cultures activated by limiting BCR:CD21 ligand and IL-4, delayed signals from BAFF and APRIL heightened COX-2 expression and ensuing PGE2 production from replicating blasts (Mongini et al., 2006, J. Immunol. 176:6736). The present study has begun to evaluate whether BAFF/APRIL-promoted COX-2/PGE2 contributes to quantitative/qualitative changes in human B cell expression of activation-induced cytosine deaminase (AID). This possibility was suggested from observations of others that BAFF and APRIL upregulate AID and promote isotype switching andexogenous PGE2 promotes the heightened production of IgG and IgE in murine B cell cultures stimulated by LPS and IL-4. Present studies with CFSE-labeled human B2 cells activated by BCR:CD21L, IL-4, and BAFF/APRIL indicate that by day 6 of culture, replicating blasts express significantly elevated levels of AID protein, while activated but non-replicating cells do not. AID levels were highest in daughter cells that had undergone the most divisions. While exogenously added PGE2 increased the level of AID detected within replicating blasts, COX-2 function was not essential for AID expression since COX-2 inhibitors did not block AID upregulation. Whether PGE2 may modulate the phosphorylation (activation) status of the expressed AID is being investigated. In sites of chronic inflammation, BAFF/APRIL-upregulated PGE2 in activated B cells might contribute to isotype switching and somatic hypermutation in the Ig locus, and potentially, lymphomagenic mutations in oncogenes.