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B lymphocyte stimulator (BLyS), a member of the tumor necrosis factor ligand superfamily, has potent costimulatory activity on B cells. To investigate BLyS signaling in Ig class switching, we examined whether BLyS could control stress-activated protein kinases in human B cells as well as whether BLyS could induce human Ig class switch recombination (CSR) and expression of activation-induced cytidine deaminase (AID). BLyS induced the phosphorylation p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in human B cells. As evidence of Ig class switch, BLyS plus interleukin (IL)-4 induced generation of switch circle transcripts (CTs) to γ 1–2, γ 4, and epsilon, whereas BLyS plus IL-10 induced γ 1–2 CTs only. BLyS strongly induced AID expression in the presence of IL-4. Treatment with SB203580, a specific inhibitor of p38 MAPK signaling, almost completely reversed BLyS-induced CSR and AID expression in human B cells. The switch vector assay also showed that BLyS induced CSR in the presence of IL-4 in Ramos 2G6 human B cells and that SB203580 reversed CSR. These results indicate that BLyS-activated p38 MAPK plays an essential role in BLyS-induced AID-expression and CSR in human B cells.