Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival.
Brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is also known to exert an antiapoptotic effect in myeloma cells. Whereas BDNF secretion was described in B lymphocytes, the ability of B cells to produce sortilin, its transport protein, was not previously reported. We studied BDNF production and the expression of its receptors, tyrosine protein kinase receptor B and p75 neurotrophin receptor in the human pre-B, mature, and plasmacytic malignant B cell lines under normal and stress culture conditions (serum deprivation, Fas activation, or their combination). BDNF secretion was enhanced by serum deprivation and exerted an antiapoptotic effect, as demonstrated by neutralization experiments with antagonistic Ab. The precursor form, pro-BDNF, also secreted by B cells, decreases under stress conditions in contrast to BDNF production. Stress conditions induced the membranous expression of p75 neurotrophin receptor and tyrosine protein kinase receptor B, maximal in mature B cells, contrasting with the sequestration of both receptors in normal culture. By blocking Ab and small interfering RNA, we evidenced that BDNF production and its survival function are depending on sortilin, a protein regulating neurotrophin transport in neurons, which was not previously described in B cells. Therefore, in mature B cell lines, an autocrine BDNF production is up-regulated by stress culture conditions and exerts a modulation of apoptosis through the sortilin pathway. This could be of importance to elucidate certain drug resistances of malignant B cells. In addition, primary B lymphocytes contained sortilin and produced BDNF after mitogenic activation, which suggests that sortilin and BDNF might be implicated in the survival and activation of normal B cells also.
Fauchais
Anne-Laure
AL
Equipe Accueil 3842, France.
Lalloué
Fabrice
F
Lise
Marie-Claude
MC
Boumediene
Ahmed
A
Preud'homme
Jean-Louis
JL
Vidal
Elisabeth
E
Jauberteau
Marie-Odile
MO
D033942:Adaptor Proteins, Vesicular Transport; D017209:Apoptosis; D019898:Autocrine Communication; D001402:B-Lymphocytes / Q000166:cytology* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020794:Receptor Protein-Tyrosine Kinases; D020800:Receptor, Nerve Growth Factor; D000099183:Sortilin