A cyclooxygenase-2 (COX-2) pathway promotes expression of activation-induced cytosine deaminase (AID) within replicating human B cells (84.7)

Abstract

Abstract Within an inflammatory milieu, B cells specific for autoantigens or microorganisms can develop tertiary lymphoid foci exhibiting AID, downstream class switching, somatic mutation, and occasionally malignant transformation. This study has examined whether COX-2, recently found elevated within cycling human B lymphoblasts, can contribute to the above. We report that after stimulation with surrogate C3dg-bound Ag, IL-4 and BAFF, CFSE-labeled IgM+ human B cells develop clones expressing division-dependent AID, accompanied by elevated levels of mPGES-1 (an inducible prostaglandin E2 (PGE2) synthase), and the PGE2 receptor, EP2. The contemporaneous expression of these proteins was functionally relevant. Thus, COX-2 inhibitors diminished both AID and class switching to IgG. Furthermore, exogenous PGE2, or selective EP2 agonist, increased AID protein. While PGE2 supplementation consistently augmented daughter cell viability and absolute yield of IgG+ progeny, somewhat surprisingly, within cultures showing higher baseline IgG switching, added PGE2 diminished the proportion of IgG+ viable progeny. Available data suggest that while PGE2-augmented AID promotes IgG switching, this process may also lead to greater activation-induced death. Taken together, these novel findings show that during a T cell-independent burst of proliferation, B cells can upregulate both AID and several COX-2 pathway proteins that constitute a positive amplification route for AID expression.