CD40 inhibits B cell apoptosis by upregulating bcl-xL expression and blocking oxidant accumulation.
Signaling through the CD40 receptor on human and murine B lymphocytes is necessary for germinal center formation and immunoglobulin class switching in vivo and rescues B cells from apoptosis triggered by cross-linking of surface immunoglobulin M in vitro. Ligation of CD40 on the immature mouse B cell line WEHI-231 with recombinant CD40 ligand (CD40L) was found to protect cells from apoptosis after gamma irradiation, as well as that following treatment with the sphingomyelin ceramide or compounds that deplete intracellular glutathione. CD40 signaling led to a rapid increase in the expression of the apoptosis inhibitory protein Bcl-xL. In addition, the apoptosis-induced accumulation of intracellular oxidants in WEHI-231 B cells was rapidly diminished by CD40 crosslinking. This antioxidant response was observed within 1 h and coincided with a preservation of intracellular thiols. These findings indicate that CD40 signaling induces a generalized cellular resistance to apoptosis characterized by an upregulation of Bcl-xL and changes in the intracellular redox potential.
Fang
W
W
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Nath
K A
KA
Mackey
M F
MF
Noelle
R J
RJ
Mueller
D L
DL
Behrens
T W
TW
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002460:Cell Line; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D013438:Sulfhydryl Compounds; D051020:bcl-X Protein; D023201:CD40 Ligand