Promotion of activated human B cell apoptosis and inhibition of Ig production by soluble CD95 ligand: CD95-based downregulation of Ig production need not culminate in activated B cell death.
CD95/CD95L interactions are vital to normal lymphoid homeostasis and in the protection against autoimmunity. To directly assess the effects of CD95L on activated B cell survival and Ig responses, purified human peripheral blood B cells, activated in vitro with SAC + rIL2, were incubated with a soluble CD95L fusion protein (fp) and assayed for apoptosis and IgG/IgM production. CD95L fp reproducibly increased apoptosis of these activated B cells and inhibited their Ig production. However, CD95L fp-mediated effects on activated B cell survival could be uncoupled from those on Ig production in that a soluble CD40L fp was incapable of reversing CD95L fp-mediated downregulation of Ig responses despite inhibiting CD95L fp-mediated apoptosis. Moreover, despite the specific caspase-8 inhibitor z-IETD-fmk substantially protecting transformed CL-01 B cells from CD95L fp-mediated apoptosis and permitting their ongoing proliferation, caspase-8 inhibition had no protective effects on CD95L fp-mediated inhibition of constitutive IgM production by CL-01 B cells. Collectively, these results point to a CD95-based downregulatory pathway in activated B cells that need not necessarily culminate in their death.
Department of Medicine, University of Southern California, Los Angeles, California 90033, USA.
W
W
Stohl
D
D
Xu
G C
GC
Starling
P
P
Casali
P A
PA
Kiener
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D017304:Annexin A5 / Q000302:isolation & purification; D015703:Antigens, CD; D018951:Antigens, CD20 / Q000302:isolation & purification; D000943:Antigens, Differentiation / Q000302:isolation & purification; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D002470:Cell Survival; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000302:isolation & purification; D011993:Recombinant Fusion Proteins; D012995:Solubility; D019014:fas Receptor / Q000302:isolation & purification
D017304:Annexin A5; D015703:Antigens, CD; D018951:Antigens, CD20; D000943:Antigens, Differentiation; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1