期刊
JOURNAL OF IMMUNOLOGY
卷 176, 期 11, 页码 6736-6751出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.11.6736
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资金
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI052189] Funding Source: NIH RePORTER
- Intramural NIH HHS Funding Source: Medline
- NIAID NIH HHS [R01 AI052189] Funding Source: Medline
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 PGE(2) synthesis, within replicating cells. Supernatants of cultures with BAFF and APRIL contained elevated PGE(2). Although COX-2 inhibitors diminished daughter cell viability, exogenous PGE(2) (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 -> PGE(2) -> Mcl-1 pathway reduces activation-related, mitochondrial apoptosis in replicating human B2 cell clones.
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