Plasma cells induce apoptosis of pre-B cells by interacting with bone marrow stromal cells.
By using two-color phenotypic analysis with fluorescein isothiocyanate-anti-CD38 and phycoerythrin-anti-CD19 antibodies, we found that pre-B cells (CD38+CD19+) signifcantly decreased depending on the number of plasma cells (CD38++CD19+) in the bone marrow (BM) in the cases with BM plasmacytosis, such as myelomas and even polyclonal gammopathy. To clarify how plasma cells suppress survival of pre-B cells, we examined the effect of plasma cells on the survival of pre-B cells with or without BM-derived stromal cells in vitro. Pre-B cells alone rapidly entered apoptosis, but interleukin-7 (IL-7), a BM stromal cell line (KM-102), or culture supernatants of KM-102 cells could support pre-B cell survival. On the other hand, inhibitory factors such as transforming growth factor-beta1 (TGF-beta1) and macrophage inflammatory protein-1beta (MIP-1beta) could suppress survival of pre-B cells even in the presence of IL-7. Plasma cells alone could not suppress survival of pre-B cells in the presence of IL-7, but coculture of plasma cells with KM-102 cells or primary BM stromal cells induced apoptosis of pre-B cells. Supernatants of coculture with KM-102 and myeloma cell lines (KMS-5) also could suppress survival of pre-B cells. Furthermore, we examined the expression of IL-7, TGF-beta1, and MIP-1beta mRNA in KM-102 cells and primary stromal cells cocultured with myeloma cell lines (KMS-5). In these cells, IL-7 mRNA was downregulated, but the expression of TGF-beta1 and MIP-1beta mRNA was augmented. Therefore, these results suggest that BM-derived stromal cells attached to plasma (myeloma) cells were modulated to secrete lesser levels of supporting factor (IL-7) and higher levels of inhibitory factors (TGF-beta1 and MIP-1beta) for pre-B cell survival, which could explain why the increased number of plasma (myeloma) cells induced suppression of pre-B cells in the BM. This phenomenon may represent a feedback loop between pre-B cells and plasma cells via BM stromal cells in the BM.
Tsujimoto
T
T
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Lisukov
I A
IA
Huang
N
N
Mahmoud
M S
MS
Kawano
M M
MM
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018941:Antigens, CD19 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes; D001483:Base Sequence; D001854:Bone Marrow Cells; D002450:Cell Communication; D002478:Cells, Cultured; D054407:Chemokine CCL4; D018920:Coculture Techniques; D003238:Connective Tissue / Q000502:physiology; D003239:Connective Tissue Cells; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology*; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics; D019402:Macrophage Inflammatory Proteins; D008969:Molecular Sequence Data; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D009101:Multiple Myeloma / Q000473:pathology; D009699:N-Glycosyl Hydrolases / Q000032:analysis; D010950:Plasma Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D054407:Chemokine CCL4; D015851:Interleukin-7; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1