title: APRIL and BAFF promote increased viability of replicating human B2 cells via mechanism involving cyclooxygenase 2.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Rheumatology, New York University Hospital for Joint Diseases, New York University Medical Center, New York, NY 10003, USA. patricia.mongini@med.nyu.edu
authors.forename: Patricia K A
authors.initials: PK
authors.lastname: Mongini
authors.forename: John K
authors.initials: JK
authors.lastname: Inman
authors.forename: Hanna
authors.initials: H
authors.lastname: Han
authors.forename: Rasem J
authors.initials: RJ
authors.lastname: Fattah
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
authors.forename: Mukundan
authors.initials: M
authors.lastname: Attur
mesh_terms: D000293:Adolescent; D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D016861:Cyclooxygenase Inhibitors; D007106:Immune Sera; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D018124:Receptors, Tumor Necrosis Factor; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2