Abstract
Cytokines exert multiple biological functions through binding to their specific receptors that triggers activation of intracellular signaling cascades. The cytokine-mediated signals may produce variable and even opposing effects on different cell types, depending on cellular context, which also are dictated by the differentiation stage of the cell. Multiple myeloma is a monoclonal proliferative disorder of human plasma cells. Despite their clonal origin, myeloma cells appear to include mixed subpopulations in accordance with expression of their surface antigens, such as CD45, CD49e, and MPC-1. Although interleukin-6 (IL-6) is widely accepted as the most relevant growth factor for myeloma cells in vitro and in vivo, only a few subpopulations of tumor cells, such as CD45+MPC-1-CD49e- immature cells, proliferate in response to IL-6.We recently showed that IL-6 efficiently activated both signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) in CD45- myeloma cell lines, although CD45- cells failed to proliferate in response to IL-6. In contrast, src family protein-tyrosine kinases (PTKs), the most important substrates for CD45 protein-tyrosine phosphatase (PTP) are found activated independently of STAT3 and ERK1/2 activation in CD45+ but not in CD45- myeloma cell lines.Therefore activation of both STAT3 and ERK1/2 is not sufficient for IL-6—induced proliferation of myeloma cells, which requires the src family kinase activation associated with CD45 expression. We propose a mechanism for IL-6—induced cell proliferation that is strictly dependent on the cellular context in myelomas.
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Li L, Dixon JE. Form, function, and regulation of protein tyrosine phosphatases and their involvement in human diseases.Semin Immunol. 2000;12:75–84.
Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.Nature. 1988;332:83–85.
Kawano MM, Huang N, Harada H, et al. Identification of immature and mature myeloma cells in the bone marrow of human myeloma.Blood. 1993;82:564–570.
Fujii R, Ishikawa H, Mahmoud MS, Asaoku H, Kawano MM. MPC-1-CD49e- immature myeloma cells include CD45+ subpopulations that can proliferate in response to IL-6 in human myelomas.Br J Haematol. 1999;105:131–140.
Ishikawa H, Tsuyama N, Abroun S, et al. Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6.Blood. 2002;99:2172–2178.
Huang N, Kawano MM, Harada H, et al. Heterogeneous expression of a novel MPC-1 antigen on myeloma cells: possible involvement of MPC-1 antigen in the adhesion of mature myeloma cells to bone marrow stromal cells.Blood. 1993;82:3721–3729.
Harada H, Kawano MM, Huang N, et al. Phenotypic difference of normal plasma cells from mature myeloma cells.Blood. 1993;81:2658–2663.
Harada Y, Kawano MM, Huang N, et al. Identification of early plasma cells in peripheral blood and their clinical significance.Br J Haematol. 1996;92:184–191.
Mahmoud MS, Huang N, Nobuyoshi M, Lisukov IA, Tanaka H, Kawano MM. Altered expression of Pax-5 gene in human myeloma cells.Blood. 1996;87:4311–4315.
Mahmoud MS, Fujii R, Ishikawa H, Kawano MM. Enforced CD19 expression leads to growth inhibition and reduced tumorigenicity.Blood. 1999;94:3551–3558.
Georgii-Hemming P, Wiklund HJ, Ljunggren O, Nilsson K. Insulinlike growth factor I is a growth and survival factor in human multiple myeloma cell lines.Blood. 1996;88:2250–2258.
Lu ZY, Zhang XG, Rodriguez C, et al. Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells.Blood. 1995;85:2521–2527.
Brenne A-T, Baade Ro T, Waage A, Sundan A, Borset M, Hjorth-Hansen H. Interleukin-21 is a growth and survival factor for human myeloma cells.Blood. 2002;99:3756–3762.
Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine.Adv Immunol. 1993;54:1–78.
Zhang XG, Bataille R, Widjenes J, Klein B. Interleukin-6 dependence of advanced malignant plasma cell dyscrasia.Cancer. 1992;69:1373–1376.
Suematsu S, Matsusaka T, Matsuda T, et al. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice.Proc Natl Acad Sci U S A. 1992;89:232–235.
Lattanzio G, Libert C, Aquilina M, et al. Defective development of pristane-oil—induced plasmacytomas in interleukin-6-deficient BALB/c mice.Am J Pathol. 1997;151:689–696.
Hilbert DM, Kopf M, Mock BA, Kohler G, Rudikoff S. Interleukin 6 is essential for in vivo development of B lineage neoplasms.J Exp Med. 1995;182:243–248.
Kawano MM, Mihara K, Huang N, Tsujimoto T, Kuramoto A. Differentiation of early plasma cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis.Blood. 1995;85:487–494.
Zhang XG, Gu JJ, Lu ZY, et al. Ciliary neutropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130.J Exp Med. 1994;179:1337–1342.
Klein B, Zhang X-G, Content J, et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6.Blood. 1989;73:517–526.
Rettig MB, Ma HJ, Vesico RA, et al. Kaposi’s sarcoma—associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.Science. 1997;276:1851–1854.
Chow D, He X, Snow AL, Rose-John S, Garcia KC. Structure of an extracellular gp130 cytokine receptor signaling complex.Science. 2001;291:2150–2155.
Mullberg J, Dittrich E, Graeve L, et al. Differential shedding of the two subunits of the interleukin-6 receptor.FEBS Lett. 1992;332:174–178.
Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor.Cytokine. 1992;4:96–100.
Kishimoto T, Taga T, Akira S. Cytokine signal transduction.Cell. 1994;76:253–262.
Taniguchi T. Cytokine signal through nonreceptor protein tyrosine kinases.Science. 1995;268:251–255.
Ihle JN. STATs: signal transducers and activators of transcription.Cell. 1996;84:331–334.
Endo TA, Masuhara M,Yokouchi M, et al. A new protein containing an SH2 domain that inhibits JAK kinases.Nature. 1997;387:921–924.
Naka T, Narazaki M, Hirata M, et al. Structure and function of a new STAT-induced STAT inhibitor.Nature. 1997;387:924–929.
Yoshimura A, Ohkubo T, Kiguchi T, et al. A novel cytokine inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors.EMBO J. 1995;14:2816–2826.
Hirano T, Matsuda T, Nakajima K. Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily.Stem Cells. 1994;12:262–277.
Ihle JN, Witthuhn BA, Quelle FW, et al. Signaling by the cytokine receptor superfamily: JAKs and STATs.Trends Biochem Sci. 1994;19:222–227.
Wen Z, Zhong Z, Darnell Jr JE. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation.Cell. 1995;82:241–250.
Fukada T, Hibi M, Yamanaka Y, et al. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis.Immunity. 1996;5:449–460.
Takahashi-Tezuka M, Yoshida Y, Fukada T, et al. Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase.Mol Cell Biol. 1998;18:4109–4117.
Dorsch M, Fan PD, Danial NN, Rothman PB, Goff SP. The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway.J Exp Med. 1997;186:1947–1955.
Chaturvedi P, Reddy MVR, Reddy EP. Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation.Oncogene. 1998;16:1749–1758.
Corey SJ, Dombrosky-Ferlan PM, Zuo S, et al. Requirement of src kinase lyn for induction of DNA synthesis by granulocyte colonystimulating factor.J Biol Chem. 1998;273:3230–3235.
Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O. Lyn physically associates with the erythropoietin and may play a role in activation of the Stat5 pathway.Blood. 1998;91:3734–3745.
Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of Stat3-related protein in cells transformed by the Src oncoprotein.Science. 1995;269:81–83.
Yu CL, Jove R, Burakoff SJ. Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase.J Immunol. 1997;159:5206–5210.
Turkson J, Bowman T, Garcia R, Caldenhoven E, DeGroot RP, Jove R. Stat3 activation by Src induces specific gene regulation and is required for cell transformation.Mol Cell Biol. 1998;18:2545–2552.
Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr. Stat3 activation is required for cellular transformation by v-src.Mol Cell Biol. 1998;18:2553–2558.
Bjorge JD, Jakymiw A, Fujita DJ. Selected glimpses into the activation and function of Src kinase.Oncogene. 2000;19:5620–5635.
Nada S, Okada M, MacAuley A, Cooper JA, Nakagawa H. Cloning of a complementary DNA for a protein tyrosine kinase that specifically phosphorylates a negative regulatory p60c-src.Nature. 1991;351:69–72.
Hatakeyama M, Kono T, Kobayashi N, et al. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association.Science. 1991;252:1523–1528.
Ernst M, Gearing DP, Dunn AR. Functional and biochemical association of hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells.EMBO J. 1994;13:1574–1584.
Anderson SM, Jorgensen B. Activation of src-related tyrosine kinases by IL-3.J Immunol. 1995;155:1660–1670.
Appleby MW, Kerner JD, Chien S, Maliszewski CR, Bondada S, Perlmutter RM. Involvement of p59fynT in interleukin-5 receptor signaling.J Exp Med. 1995;182:811–820.
Pazdrak K, Schreiber D, Forsythe P, Justement L, Alam R. The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the ras-raf-1-MEK-microtubule—associated protein kinase pathway.J Exp Med. 1995;181:1827–1834.
Corey S, Eguinoa A, Puyana TK, et al. Granulocyte macrophagecolony stimulating factor stimulates both association and activation of phosphoinositide 3OH-kinase and src-related tyrosine kinase(s) in human myeloid derived cells.EMBO J. 1993;12:2681–2690.
Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ. Granulocyte-colony stimulating factor receptor signaling involves the formation of a three component complex with lyn and syk protein-tyrosine kinases.Proc Natl Acad Sci U S A. 1994;91:4683–4687.
Hallek M, Neumann C, Schaffer M, et al. Signal transduction of interleukin-6 involves tyrosine phosphorylation of multiple cytosolic proteins and activation of Src-family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines.Exp Hematol. 1997;25:1367–1377.
Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H. Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens.J Exp Med. 1987;166:1548–1566.
Charbonneau H, Tonks NK, Walsh KA, Fischer EH. The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase.Proc Natl Acad Sci U S A. 1988;85:7182–7186.
Trowbridge IS, Thomas ML. CD45: an emerging role as a protein phosphatase required for lymphocyte activation and development.Annu Rev Immunol. 1994;12:85–116.
Reth M, Wienands J. Initiation and processing of signals from the B cell antigen receptor.Annu Rev Immunol. 1997;15:453–479.
Kishihara K, Penninger J, Wallace VA, et al. Normal B lymphocyte development but impaired T cell maturation in CD45-exon 6 protein tyrosine phosphatase-deficient mice.Cell. 1993;74:143–156.
Kung C, Pingel JT, Heikinheimo M, et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease.Nat Med. 2000;6:343–345.
Seavitt JR, White LS, Murphy KM, Loh DY, Perlmutter RG, Thomas ML. Expression of the p56lck Y505F mutation in CD45-deficient mice rescues thymocyte development.Mol Cell Biol. 1999;19:4200–4208.
Irie-Sasaki J, Sasaki T, Matsumoto W, et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling.Nature. 2001;409:349–354.
van der Merwe PA, Davis SJ, Shaw AS, Dustin ML. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.Semin Immunol. 2000;12:5–21.
Janes PW, Ley SC, Magee AI, Kabouridis PS. The role of lipid rafts in T cell antigen receptor (TCR) signalling.Semin Immunol. 2000;12:23–34.
Desai DM, Sap J, Schlessinger J, Weiss A. Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase.Cell. 1993;73:541–554.
Jiang G, den Hertog J, Su J, Noel J, Sap J, Hunter T. Dimerization inhibits the activity of receptor-like protein tyrosine phosphatasealpha.Nature. 1999;401:606–610.
Majeti R, Xu Z, Parslow TG, et al. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity.Cell. 2000;103:1059–1070.
Hata H, Matsuzaki H, Sonoki T, et al. Establishment of a CD45-positive immature plasma cell line from an aggressive multiple myeloma with high serum lactate dehydrogenase.Leukemia. 1994;8:1768–1773.
Witzig TE, Kimlinger TK, Ahmann GJ, et al. Detection of myeloma cells in the peripheral blood by flow cytometry.Cytometry. 1996;26:113–120.
Joshua D, Peterson A, Brown R, et al. The labelling index of primitive plasma cells determines the clinical behaviour of patients with myelomatosis.Br J Haematol. 1996;94:76–81.
Schneider U, van Lessen A, Huhn D, et al. Two subsets of peripheral blood plasma cells defined by differential expression of CD45 antigen.Br J Haematol. 1997;97:56–64.
Lynch KW, Weiss A. A model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates PKC and Ras.Mol Cell Biol. 2000;20:70–80.
Kawano MM, Mahmoud MS, Ishikawa H. Cyclin D1 and p16INK4A are preferentially expressed in immature and mature myeloma cells, respectively.Br J Haematol. 1997;99:131–138.
Mahmoud MS, Ishikawa H, Fujii R, Kawano MM. Induction of CD45 expression and proliferation in U-266 myeloma cell line by interleukin-6.Blood. 1998;92:3887–3897.
Dong F, Larner AC. Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the janus kinase.Blood. 2000;95:1656–1662.
Corey SJ, Anderson SM. Src-related protein tyrosine kinases in hematopoiesis.Blood. 1999;93:1–14.
Schwabe M, Brini AT, Bosco MC, et al. Disruption by interferon-α of an autocrine interleukin-6 growth loop in IL-6-dependent U266 myeloma cells by homologous and heterologous down-regulation of IL-6 receptor α- and β-chains.J Clin Invest. 1994;94:2317–2325.
Ishikawa H, Tanaka H, Iwato K, et al. Effect of glucocorticoids on the biologic activities of plasma cells: Inhibition of interleukin-1β osteoclast activating factor-induced bone resorption.Blood. 1990;75:715–720.
Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia.Blood. 1991;78:1198–1204.
Suzuki H, Yasukawa K, Saito T, et al. Anti-human interleukin-6 receptor antibody inhibits human myeloma growth in vivo.Eur J Immunol. 1992;22:1989–1993.
Sato K, Tsuchiya M, Saldanha J, et al. Reshaping a human antibody to inhibit interleukin-6 dependent tumor cell growth.Cancer Res. 1993;53:851–856.
Ihara S, Nakajima K, Fukada T, et al. Dual control of neurite outgrowth by STAT3 and MAP kinase in PC12 cells stimulated with interleukin-6.EMBO J. 1997;16:5345–5352.
Qiu Y, Ravi L, Kung H-J. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells.Nature. 1998;393:83–85.
Nakashima K, Yanagisawa M, Arakawa H, et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.Science. 1999;284:479–482.
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Ishikawa, H., Tsuyama, N. & Kawano, M.M. Interleukin-6—Induced Proliferation of Human Myeloma Cells Associated with CD45 Molecules. Int J Hematol 78, 95–105 (2003). https://doi.org/10.1007/BF02983376
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DOI: https://doi.org/10.1007/BF02983376