BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1.
BACKGROUND
Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and are secreted proteins with pleiotropic roles in many different cell types. A potential role of BMP-6 in the immune system has been implied by various studies of malignant and rheumatoid diseases. In the present study, we explored the role of BMP-6 in normal human peripheral blood B cells.


RESULTS
The B cells were found to express BMP type I and type II receptors and BMP-6 rapidly induced phosphorylation of Smad1/5/8. Furthermore, Smad-phosphorylation was followed by upregulation of Id1 mRNA and Id1 protein, whereas Id2 and Id3 expression was not affected. Furthermore, we found that BMP-6 had an antiproliferative effect both in naive (CD19+CD27-) and memory B cells (CD19+CD27+) stimulated with anti-IgM alone or the combined action of anti-IgM and CD40L. Additionally, BMP-6 induced cell death in activated memory B cells. Importantly, the antiproliferative effect of BMP-6 in B-cells was completely neutralized by the natural antagonist, noggin. Furthermore, B cells were demonstrated to upregulate BMP-6 mRNA upon stimulation with anti-IgM.


CONCLUSIONS
In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1/5/8 followed by an upregulation of Id1.
Kersten
Christian
C
Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. christian.kersten@sshf.no
Sivertsen
Einar A
EA
Hystad
Marit E
ME
Forfang
Lise
L
Smeland
Erlend B
EB
Myklebust
June H
JH
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D055418:Bone Morphogenetic Protein 6; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002051:Burkitt Lymphoma / Q000473:pathology; D023201:CD40 Ligand / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D051904:Smad8 Protein / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000888:Antibodies, Anti-Idiotypic; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C044203:anti-IgM; D023201:CD40 Ligand; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II