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BMC Immunology
Published in: BMC Immunology 1/2005

Open Access 01-12-2005 | Research article

BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1

Authors: Christian Kersten, Einar A Sivertsen, Marit E Hystad, Lise Forfang, Erlend B Smeland, June H Myklebust

Published in: BMC Immunology | Issue 1/2005

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Abstract

Background

Bone morphogenetic proteins (BMPs) belong to the TGF-β 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 naïve (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.

Conclusion

In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1/5/8 followed by an upregulation of Id1.
Appendix
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Literature
1.
Chen D, Zhao M, Harris SE, Mi Z: Signal transduction and biological functions of bone morphogenetic proteins. Front Biosci. 2004, 9 (349-58): 349-358.CrossRefPubMed
2.
3.
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA: Novel regulators of bone formation: molecular clones and activities. Science. 1988, 242: 1528-1534.CrossRefPubMed
4.
Kim SJ, Letterio J: Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia. 2003, 17: 1731-1737. 10.1038/sj.leu.2403069.CrossRefPubMed
5.
Bhatia M, Bonnet D, Wu D, Murdoch B, Wrana J, Gallacher L, Dick JE: Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J Exp Med. 1999, 189: 1139-1148. 10.1084/jem.189.7.1139.PubMedCentralCrossRefPubMed
6.
Hager-Theodorides AL, Outram SV, Shah DK, Sacedon R, Shrimpton RE, Vicente A, Varas A, Crompton T: Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J Immunol. 2002, 169: 5496-5504.CrossRefPubMed
7.
Graf D, Nethisinghe S, Palmer DB, Fisher AG, Merkenschlager M: The developmentally regulated expression of Twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development. J Exp Med. 2002, 196: 163-171. 10.1084/jem.20020276.PubMedCentralCrossRefPubMed
8.
Ahmed N, Sammons J, Carson RJ, Khokher MA, Hassan HT: Effect of bone morphogenetic protein-6 on haemopoietic stem cells and cytokine production in normal human bone marrow stroma. Cell Biol Int. 2001, 25: 429-435. 10.1006/cbir.2000.0662.CrossRefPubMed
9.
Kawamura C, Kizaki M, Yamato K, Uchida H, Fukuchi Y, Hattori Y, Koseki T, Nishihara T, Ikeda Y: Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood. 2000, 96: 2005-2011.PubMed
10.
Hjertner O, Hjorth-Hansen H, Borset M, Seidel C, Waage A, Sundan A: Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood. 2001, 97: 516-522. 10.1182/blood.V97.2.516.CrossRefPubMed
11.
Baade RT, Utne HR, Brenne AT, Hjorth-Hansen H, Waage A, Hjertner O, Sundan A, Borset M: Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Oncogene. 2004, 23 (17): 3024-3032. 10.1038/sj.onc.1207386.CrossRef
12.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002, 346: 1937-1947. 10.1056/NEJMoa012914.CrossRefPubMed
13.
Waite KA, Eng C: From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nat Rev Genet. 2003, 4: 763-773. 10.1038/nrg1178.CrossRefPubMed
14.
Ying QL, Nichols J, Chambers I, Smith A: BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003, 115: 281-292. 10.1016/S0092-8674(03)00847-X.CrossRefPubMed
15.
Klein U, Rajewsky K, Kuppers R: Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998, 188: 1679-1689. 10.1084/jem.188.9.1679.PubMedCentralCrossRefPubMed
16.
Aoki H, Fujii M, Imamura T, Yagi K, Takehara K, Kato M, Miyazono K: Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. J Cell Sci. 2001, 114: 1483-1489.PubMed
17.
Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K: Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells. 2002, 7: 1191-1204. 10.1046/j.1365-2443.2002.00599.x.CrossRefPubMed
18.
Grimsrud CD, Romano PR, D'Souza M, Puzas JE, Reynolds PR, Rosier RN, O'Keefe RJ: BMP-6 is an autocrine stimulator of chondrocyte differentiation. J Bone Miner Res. 1999, 14: 475-482.CrossRefPubMed
19.
Shepherd TG, Nachtigal MW: Identification of a putative autocrine bone morphogenetic protein-signaling pathway in human ovarian surface epithelium and ovarian cancer cells. Endocrinology. 2003, 144: 3306-3314. 10.1210/en.2003-0185.CrossRefPubMed
20.
Detmer K, Steele TA, Shoop MA, Dannawi H: Lineage-restricted expression of bone morphogenetic protein genes in human hematopoietic cell lines. Blood Cells Mol Dis. 1999, 25: 310-323. 10.1006/bcmd.1999.0259.CrossRefPubMed
21.
Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, Sutherland MK, Latham JA: Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J Biol Chem. 2004, 279: 36293-36298. 10.1074/jbc.M400521200.CrossRefPubMed
22.
Haudenschild DR, Palmer SM, Moseley TA, You Z, Reddi AH: Bone morphogenetic protein (BMP)-6 signaling and BMP antagonist noggin in prostate cancer. Cancer Res. 2004, 64: 8276-8284.CrossRefPubMed
23.
Xu WP, Shiba H, Mizuno N, Uchida Y, Mouri Y, Kawaguchi H, Kurihara H: Effect of bone morphogenetic proteins-4, -5 and -6 on DNA synthesis and expression of bone-related proteins in cultured human periodontal ligament cells. Cell Biol Int. 2004, 28: 675-682. 10.1016/j.cellbi.2004.06.004.CrossRefPubMed
24.
Song JJ, Celeste AJ, Kong FM, Jirtle RL, Rosen V, Thies RS: Bone morphogenetic protein-9 binds to liver cells and stimulates proliferation. Endocrinology. 1995, 136: 4293-4297. 10.1210/en.136.10.4293.PubMed
25.
Otsuka F, Yao Z, Lee T, Yamamoto S, Erickson GF, Shimasaki S: Bone morphogenetic protein-15. Identification of target cells and biological functions. J Biol Chem. 2000, 275: 39523-39528. 10.1074/jbc.M007428200.CrossRefPubMed
26.
Ishisaki A, Yamato K, Hashimoto S, Nakao A, Tamaki K, Nonaka K, ten Dijke P, Sugino H, Nishihara T: Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem. 1999, 274: 13637-13642. 10.1074/jbc.274.19.13637.CrossRefPubMed
27.
Nohe A, Keating E, Knaus P, Petersen NO: Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2004, 16: 291-299. 10.1016/j.cellsig.2003.08.011.CrossRefPubMed
28.
Nakahara T, Tominaga K, Koseki T, Yamamoto M, Yamato K, Fukuda J, Nishihara T: Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad. Cell Signal. 2003, 15: 181-187. 10.1016/S0898-6568(02)00088-8.CrossRefPubMed
29.
Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T: BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem. 2000, 275: 17647-17652. 10.1074/jbc.M908622199.CrossRefPubMed
30.
Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T: Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999, 284: 479-482. 10.1126/science.284.5413.479.CrossRefPubMed
31.
Valdimarsdottir G, Goumans MJ, Rosendahl A, Brugman M, Itoh S, Lebrin F, Sideras P, ten Dijke P: Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation. 2002, 106: 2263-2270. 10.1161/01.CIR.0000033830.36431.46.CrossRefPubMed
32.
Ruzinova MB, Benezra R: Id proteins in development, cell cycle and cancer. Trends Cell Biol. 2003, 13: 410-418. 10.1016/S0962-8924(03)00147-8.CrossRefPubMed
33.
Saisanit S, Sun XH: Regulation of the pro-B-cell-specific enhancer of the Id1 gene involves the C/EBP family of proteins. Mol Cell Biol. 1997, 17: 844-850.PubMedCentralCrossRefPubMed
34.
Wilson RB, Kiledjian M, Shen CP, Benezra R, Zwollo P, Dymecki SM, Desiderio SV, Kadesch T: Repression of immunoglobulin enhancers by the helix-loop-helix protein Id: implications for B-lymphoid-cell development. Mol Cell Biol. 1991, 11: 6185-6191.PubMedCentralCrossRefPubMed
35.
Sun XH: Constitutive expression of the Id1 gene impairs mouse B cell development. Cell. 1994, 79: 893-900. 10.1016/0092-8674(94)90078-7.CrossRefPubMed
36.
Kee BL, Rivera RR, Murre C: Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nat Immunol. 2001, 2: 242-247. 10.1038/85303.CrossRefPubMed
37.
Sugai M, Gonda H, Kusunoki T, Katakai T, Yokota Y, Shimizu A: Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol. 2003, 4: 25-30. 10.1038/ni874.CrossRefPubMed
38.
Sugai M, Gonda H, Nambu Y, Yokota Y, Shimizu A: Role of Id proteins in B lymphocyte activation: new insights from knockout mouse studies. J Mol Med. 2004, 2 (9): 592-599.
39.
Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM: Id proteins in cell growth and tumorigenesis. Cancer Cell. 2003, 3: 525-530. 10.1016/S1535-6108(03)00141-7.CrossRefPubMed
40.
Engel I, Murre C: The function of E- and Id proteins in lymphocyte development. Nat Rev Immunol. 2001, 1: 193-199. 10.1038/35105060.CrossRefPubMed
41.
Sikder HA, Devlin MK, Dunlap S, Ryu B, Alani RM: Id proteins in cell growth and tumorigenesis. Cancer Cell. 2003, 3: 525-530. 10.1016/S1535-6108(03)00141-7.CrossRefPubMed
42.
Norton JD: ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci. 2000, 113: 3897-3905.PubMed
43.
Gortz B, Hayer S, Redlich K, Zwerina J, Tohidast-Akrad M, Tuerk B, Hartmann C, Kollias G, Steiner G, Smolen JS, Schett G: Arthritis induces lymphocytic bone marrow inflammation and endosteal bone formation. J Bone Miner Res. 2004, 19: 990-998.CrossRefPubMed
44.
Lories RJ, Derese I, Ceuppens JL, Luyten FP: Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Arthritis Rheum. 2003, 48: 2807-2818. 10.1002/art.11389.CrossRefPubMed
45.
Sakurai D, Yamaguchi A, Tsuchiya N, Yamamoto K, Tokunaga K: Expression of ID family genes in the synovia from patients with rheumatoid arthritis. Biochem Biophys Res Commun. 2001, 284: 436-442. 10.1006/bbrc.2001.4974.CrossRefPubMed
46.
Bobacz K, Gruber R, Soleiman A, Erlacher L, Smolen JS, Graninger WB: Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum. 2003, 48: 2501-2508. 10.1002/art.11248.CrossRefPubMed
47.
Schiemann WP, Pfeifer WM, Levi E, Kadin ME, Lodish HF: A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma. Blood. 1999, 94: 2854-2861.PubMed
48.
Yotnda P, Garcia F, Peuchmaur M, Grandchamp B, Duval M, Lemonnier F, Vilmer E, Langlade-Demoyen P: Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia. J Clin Invest. 1998, 102: 455-462.PubMedCentralCrossRefPubMed
49.
Wach S, Schirmacher P, Protschka M, Blessing M: Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members. Oncogene. 2001, 20: 7761-7769. 10.1038/sj.onc.1204962.CrossRefPubMed
50.
Amendt C, Schirmacher P, Weber H, Blessing M: Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development. Oncogene. 1998, 17: 25-34. 10.1038/sj.onc.1202161.CrossRefPubMed
51.
Liu Y, Titus L, Barghouthi M, Viggeswarapu M, Hair G, Boden SD: Glucocorticoid regulation of human BMP-6 transcription. Bone. 2004, 35: 673-681. 10.1016/j.bone.2004.04.017.CrossRefPubMed
52.
Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB: Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A. 2002, 99: 4465-4470. 10.1073/pnas.012025199.PubMedCentralCrossRefPubMed
53.
Glienke J, Schmitt AO, Pilarsky C, Hinzmann B, Weiss B, Rosenthal A, Thierauch KH: Differential gene expression by endothelial cells in distinct angiogenic states. Eur J Biochem. 2000, 267: 2820-2830. 10.1046/j.1432-1327.2000.01325.x.CrossRefPubMed
54.
Champagne CM, Takebe J, Offenbacher S, Cooper LF: Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone. 2002, 30: 26-31. 10.1016/S8756-3282(01)00638-X.CrossRefPubMed
55.
Rasmussen AM, Smeland EB, Erikstein BK, Caignault L, Funderud S: A new method for detachment of Dynabeads from positively selected B lymphocytes. J Immunol Methods. 1992, 146: 195-202. 10.1016/0022-1759(92)90228-L.CrossRefPubMed
56.
Lossos IS, Czerwinski DK, Wechser MA, Levy R: Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies. Leukemia. 2003, 17: 789-795. 10.1038/sj.leu.2402880.CrossRefPubMed
Metadata
Title
BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1
Authors
Christian Kersten
Einar A Sivertsen
Marit E Hystad
Lise Forfang
Erlend B Smeland
June H Myklebust
Publication date
01-12-2005
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2005
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-6-9

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