B lymphocyte stimulator activates p38 mitogen-activated protein kinase in human Ig class switch recombination.
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 gamma 1-2, gamma 4, and epsilon, whereas BLyS plus IL-10 induced gamma 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.
Yamada
Takechiyo
T
Division of Clinical Immunology, Department of Medicine, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90095-1680, USA. ymdtkcy@fmsrsa.fukui-med.ac.jp
Zhang
Ke
K
Yamada
Akiko
A
Zhu
Daocheng
D
Saxon
Andrew
A
D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017578:Immunoglobulin Class Switching; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008565:Membrane Proteins; D011725:Pyridines; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase; C093642:SB 203580