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Role of Endogenous Brain-Derived Neurotrophic Factor and Sortilin in B Cell Survival¹

Anne-Laure Fauchais^*,, Fabrice Lalloué^*, Marie-Claude Lise^*, Ahmed Boumediene, Jean-Louis Preud'homme, Elisabeth Vidal^*, and Marie-Odile Jauberteau^2,*,

^* Equipe Accueil 3842, France; Departments of Internal Medicine and Immunology, University of Limoges, France; and Department of Immunology, University of Poitiers, France

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Association Recherche et Entraide des Maladies Lupiques.

² Address correspondence and reprint requests to Dr. Marie-Odile Jauberteau, Department of Immunology, EA 3842, University of Limoges, 2 Avenue Doctor Marcland, 87025 Limoges, France. E-mail address: m-o.jauberteau-marchan{at}unilim.fr

³ Abbreviations used in this paper: BDNF, brain-derived neurotrophic growth factor; DRG, dorsal root ganglion; MMP, matrix metalloprotease; NGF, nerve growth factor; p75^NTR, p75 neurotrophin receptor; siRNA, small interfering RNA; Trk, tyrosine protein kinase receptor.