Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 2; p. 316
• Main Authors: Flores-Fernández, Rocio, Aponte-López, Angélica, Suárez-Arriaga, Mayra C, Gorocica-Rosete, Patricia, Pizaña-Venegas, Alberto, Chávez-Sanchéz, Luis, Blanco-Favela, Francico, Fuentes-Pananá, Ezequiel M, Chávez-Rueda, Adriana K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04-02-2021; MDPI
• Subjects: Antibodies; Apoptosis; Autoimmune diseases; B-cell receptor; Bcl2a1a; Birc5; Bone marrow; Cell activation; Chromatin; Clonal deletion; Cloning; Disease; Flow cytometry; Gene regulation; immature B cells; Immunological tolerance; Immunoprecipitation; Kinases; Laboratory animals; Lupus; Lymphocytes B; Peptides; Phosphorylation; Polymerase chain reaction; Prolactin; prolactin receptor; STAT3; Stat3 protein; Systemic lupus erythematosus; Transcription activation; United States > US; Netherlands; Germany; prolactin receptor; systemic lupus erythematosus; prolactin; immature B cells; STAT3; MRL/lpr mice; Birc5; Bcl2a1a
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10020316

Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.