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APRIL and BAFF Promote Increased Viability of Replicating Human B2 Cells via Mechanism Involving Cyclooxygenase 2¹

Patricia K. A. Mongini^2,*,, John K. Inman, Hanna Han^*, Rasem J. Fattah, Steven B. Abramson^*, and Mukundan Attur^*

^* Department of Medicine, Division of Rheumatology, New York University Hospital for Joint Diseases, New York University Medical Center, New York, NY 10003; Department of Pathology, New York University Medical Center, New York, NY 10003; and Laboratory of Immunology, National Institutes of Health, Bethesda, MD 20892

Of relevance to both protective and pathogenic responses to Ag is the recent finding that soluble molecules of the innate immune system, i.e., IL-4, B cell-activation factor of the TNF family (BAFF), and C3, exhibit significant synergy in promoting the clonal expansion of human B2 cells following low-level BCR ligation. Although IL-4, BAFF, and C3dg each contribute to early cell cycle entry and progression to S phase, only BAFF promotes later sustained viability of progeny needed for continued cycling. The present study sought to further clarify the mechanisms for BAFF’s multiple functions. By comparing BAFF and a proliferation-inducing ligand (APRIL) efficacy at different stages in the response (only BAFF binds BR3; both bind transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag, the early role was attributed to BR3, while the later role was attributed to TACI/B cell maturation Ag. Importantly, BAFF- and APRIL-promoted viability of cycling lymphoblasts was associated with sustained expression of cyclooxygenase 2 (COX-2), the rate-limiting enzyme for PGE₂ synthesis, within replicating cells. Supernatants of cultures with BAFF and APRIL contained elevated PGE₂. Although COX-2 inhibitors diminished daughter cell viability, exogenous PGE₂ (1–1000 nM) increased the viability and recovery of lymphoblasts. Increased yield of viable progeny was associated with elevated Mcl-1, suggesting that a BAFF/APRIL TACI COX-2 PGE₂ Mcl-1 pathway reduces activation-related, mitochondrial apoptosis in replicating human B2 cell clones.

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				P. K. A. Mongini EFFECTS OF B CELL COX-2/PGE2 ON ACTIVATION-INDUCED CYTOSINE DEAMINASE (AID) J. Immunol., April 1, 2007; 178(MeetingAbstracts): S2 - S2.

				E. P. Ryan, C. M. Malboeuf, M. Bernard, R. C. Rose, and R. P. Phipps Cyclooxygenase-2 Inhibition Attenuates Antibody Responses against Human Papillomavirus-Like Particles J. Immunol., December 1, 2006; 177(11): 7811 - 7819. [Abstract] [Full Text] [PDF]