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Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway

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Abstract

Recently, many studies have shown that granulocyte macrophage-colony stimulating factor (GM-CSF) has anti-apoptotic activity and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. This study investigated detailed mechanism of GM-CSF involved in its anti-apoptotic activity and regulation of Bcl-2 expression in neural progenitor cells (NPCs) as a model. NPCs were cultured from the brain of E13 ICR mouse. When NPCs were treated with staurosporine at 1 μM, apoptosis occurred in more than 30% of cells in TUNEL assay. However, apoptosis was significantly inhibited by pre-treatment with GM-CSF at 10 ng/ml. Under the same experimental condition, the expression of both Bcl-2 and Bcl-xl was clearly induced by GM-CSF regardless of staurosporine treatment in RT-PCR and Western blot analyses. GM-CSF was shown to induce the expression of Bcl-2 and Bcl-xl via Janus tyrosine kinase (JAK) but not via phosphatidylinositol 3-kinase (PI3K) or RAS-mitogen activated protein kinase kinase-1 (MEK-1) using specific signal pathway inhibitors. Further analyses showed that the expression of Bcl-2 and Bcl-xl was induced by GM-CSF via signal transducers and activators of transcription 5 (STAT5) and STAT3, respectively. In addition, JAK/STAT5-Bcl-2 pathway but not JAK/STAT3-Bcl-xl pathway was responsible for the anti-apoptotic activity of GM-CSF in NPCs in TUNEL assay. To our knowledge, this study is the first report that shows differential roles of Bcl-2 and Bcl-xl, and their regulation mechanism involved in the anti-apoptotic activity of GM-CSF in NPCs.

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References

  1. de Groot RP, Coffer PJ, Koenderman L (1998) Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal 10:619–628

    Article  PubMed  Google Scholar 

  2. Kim JK, Choi BH, Park HC, Park SR, Kim YS, Yoon SH, Park H, Kim EY, Ha Y (2004) Effects of GM-CSF on the neural progenitor cells. NeuroReport 15:2161–2165

    Article  CAS  PubMed  Google Scholar 

  3. Franzen R, Bouhy D, Schoenen J (2004) Nervous system injury: focus on the inflammatory cytokine ‘granulocyte-macrophage colony stimulating factor’. Neurosci Lett 361:76–78

    Article  CAS  PubMed  Google Scholar 

  4. Kannan Y, Moriyama M, Sugano T, Yamate J, Kuwamura M, Kagaya A, Kiso Y (2000) Neurotrophic action of interleukin 3 and granulocyte-macrophage colony stimulating factor on murine sympathetic neurons. Neuroimmunomodulation 8:132–141

    Article  CAS  PubMed  Google Scholar 

  5. Lin X, Zhang Y, Dong J, Zhu X, Ye M, Shi J, Lu J, Di Q, Shi J, Liu W (2007) GM-CSF enhances neural differentiation of bone marrow stromal cells. NeuroReport 18:1113–1117

    Article  PubMed  Google Scholar 

  6. Sayani F, Montero-Julian FA, Ranchin V, Prevost JM, Flavetta S, Zhu W, Woodman RC, Brailly H, Brown CB (2000) Identification of the soluble granulocyte-macrophage colony stimulating factor receptor protein in vivo. Blood 95:461–469

    CAS  PubMed  Google Scholar 

  7. Huang X, Kim JM, Kong TH, Park SR, Ha Y, Kim MH, Park H, Yoon SH, Park HC, Park JO, Min B-H, Choi BH (2009) GM-CSF inhibits glial scar formation and shows long-term protective effect after spinal cord injury. J Neurol Sci 277:87–97

    Article  CAS  PubMed  Google Scholar 

  8. Ha Y, Kim YS, Cho JM, Yoon SH, Park SR, Yoon DH, Kim EY, Park HC (2004) Role of granulocyte macrophage colony stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury. J Neurosurg Spine 2:55–61

    Article  Google Scholar 

  9. Huang X, Choi JK, Park SR, Ha Y, Park H, Yoon SH, Park HC, Park JO, Choi BH (2007) GM-CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis-related proteins. Neurosci Res 58:50–57

    Article  CAS  PubMed  Google Scholar 

  10. Kim NK, Choi BH, Huang X, Snyder BJ, Bukhari S, Kong TH, Park H, Park HC, Park SR, Ha Y (2009) Granulocyte–macrophage colony-stimulating factor promotes survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine Parkinson’s disease model. Eur J Neurosci 29:891–900

    Article  PubMed  Google Scholar 

  11. Kong TH, Choi J-K, Park H, Choi BH, Snyder BJ, Bukhari S, Kim N-K, Huang X, Park SR, Park HC, Ha Y (2009) Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats. J Neurosurg 111:155–163

    Article  CAS  PubMed  Google Scholar 

  12. Nakagawa T, Suga S, Kawase T, Toda M (2006) Intracarotid injection of granulocyte-macrophage colony-stimulating factor induces neuroprotection in a rat transient middle cerebral artery occlusion model. Brain Res 1089:179–185

    Article  CAS  PubMed  Google Scholar 

  13. Schäbitz WR, Krüger C, Pitzer C, Weber D, Laage R, Gassler N, Aronowski J, Mier W, Kirsch F, Dittgen T, Bach A, Sommer C, Schneider A (2008) A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GMCSF). J Cereb Blood Flow Metab 28:29–43

    Article  PubMed  Google Scholar 

  14. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, Park H (2005) Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11:913–922

    Article  CAS  PubMed  Google Scholar 

  15. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR, Min BH, Kim EY, Choi BH, Park H, Ha Y (2007) Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 25:2066–2073

    Article  PubMed  Google Scholar 

  16. Burlacu A (2003) Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med 7:249–257

    Article  CAS  PubMed  Google Scholar 

  17. Rapp UR, Rennefahrt U, Troppmair J (2004) Bcl-2 proteins: master switches at the intersection of death signaling and the survival control by raf kinase. Biochem Biophys Acta 1644:149–158

    Article  CAS  PubMed  Google Scholar 

  18. Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF (1998) Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells 16:301–313

    Article  CAS  PubMed  Google Scholar 

  19. Wu C, Fujihara H, Yao J, Qi S, Li H, Shimoji K, Baba H (2003) Different expression patterns of Bcl-2, Bcl-xl, and Bax proteins after sublethal forebrain ischemia in C57Black/Crj6 mouse striatum. Stroke 34:1803–1808

    Article  CAS  PubMed  Google Scholar 

  20. Davies AM (1995) The Bcl-2 family of proteins, and the regulation of neuronal survival. Trends Neurosci 18:355–358

    Article  CAS  PubMed  Google Scholar 

  21. Blömer U, Kafri T, Randolph-Moore L, Verma IM, Gage FH (1998) Bcl-xL protects adult septal cholinergic neurons from axotomized cell death. Proc Natl Acad Sci USA 95:2603–2608

    Article  PubMed  Google Scholar 

  22. Zimmermann AK, Loucks FA, Le SS, Butts BD, Florez-McClure ML, Bouchard RJ, Heidenreich KA, Linseman DA (2005) Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl-2/Bcl-x(L) versus induction of the BH3-only protein Bim. J Neurochem 94:22–36

    Article  CAS  PubMed  Google Scholar 

  23. Kinoshita T, Yokota T, Arai K-I, Miyajima A (1995) Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3/GM-CSF receptors. EMBO J 14:266–275

    CAS  PubMed  Google Scholar 

  24. Guthridge MA, Barry EF, Felquer FA, McClure BJ, Stomski FC, Ramshaw H, Lopez AF (2004) The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kB and induction of bcl-2. Blood 103:820–827

    Article  CAS  PubMed  Google Scholar 

  25. Chong ZZ, Kang JQ, Maiese K (2002) Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cereb Blood Flow Metab 22:503–514

    Article  CAS  PubMed  Google Scholar 

  26. Schneider A, Krüger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn H-G, Schäbitz W-R (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Investig 115:2083–2098

    Article  CAS  PubMed  Google Scholar 

  27. Solaroglu I, Cahill J, Jadhav V, Zhang JH (2006) A novel neuroprotectant granulocyte-colony stimulating factor. Stroke 37:1123–1128

    Article  CAS  PubMed  Google Scholar 

  28. Tolosa L, Mir M, Olmos G, Lladó J (2009) Vascular endothelial growth factor protects motoneurons from serum deprivation-induced cell death through phosphatidylinositol 3-kinase-mediated p38 mitogen-activated protein kinase inhibition. Neuroscience 158:1348–1355

    Article  CAS  PubMed  Google Scholar 

  29. Wen TC, Sadamoto Y, Tanaka J, Zhu PX, Nakata K, Ma YJ, Hata R, Sakanaka M (2002) Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J Neurosci Res 15:795–803

    Article  Google Scholar 

  30. Wick A, Wick W, Waltenberger J, Weller M, Dichgans J, Schulz JB (2002) Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 22:6401–6407

    CAS  PubMed  Google Scholar 

  31. Klein JB, Rane MJ, Scherzer JA, Coxon PY, Kettritz R, Mathiesen JM, Buridi A, McLeish KR (2000) Granulocyte-macrophage colony-stimulating factor delays neutrophil constitutive apoptosis through phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways. J Immunol 164:4286–4291

    CAS  PubMed  Google Scholar 

  32. Kotone-Miyahara Y, Yamashita K, Lee K-K, Yonehara S, Uchiyama T, Sasada M, Takahashi A (2004) Short-term delay of Fas-stimulated apoptosis by GM-CSF as a result of temporary suppression of FADD recruitment in neutrophils: evidence implicating phosphatidylinositol 3-kinase and MEK1-ERK1/2 pathways downstream of classical protein kinase C. J Leukoc Biol 76:1047–1056

    Article  CAS  PubMed  Google Scholar 

  33. Miike S, Nakao A, Hiraguri M, Kurasawa K, Saito Y, Iwamoto I (1999) Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils. J Leukoc Biol 65:700–706

    CAS  PubMed  Google Scholar 

  34. Geng Y, Walls KC, Ghosh AP, Akhtar RS, Klocke BJ, Roth KA (2009) Cytoplasmic p53 and activated Bax regulate p53-dependent, transcription-independent neural precursor cell apoptosis. J Histochem Cytochem 58:265–275

    Article  PubMed  Google Scholar 

  35. Chao J-R, Wang J-M, Lee S-F, Peng H-W, Lin Y-H, Chou C-H, Li J-C, Huang H-M, Chou C-K, Kuo M-L, Yen JJ-Y, Yang-Yen H-F (1998) mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol 18:4883–4898

    CAS  PubMed  Google Scholar 

  36. Derouet M, Thomas L, Cross A, Moots RJ, Edwards SW (2004) Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1. J Biol Chem 279:26915–26921

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the grants of Ministry of Health and Welfare (A050082) and the Ministry of Eduction, Science and Technology (2009-0079196), Republic of Korea.

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Authors and Affiliations

  1. Department of Physiology, Inha University College of Medicine, Incheon, Korea

    Jung Kyoung Choi, Kil Hwan Kim & So Ra Park

  2. Department of Neurosurgery, Inha University College of Medicine, Incheon, Korea

    Hyeonseon Park

  3. Division of Biomedical and Bioengineering Sciences, Inha University College of Medicine, Jungseok B/D, 7-206, Sinheung-dong 3-Ga, Jung-gu, Incheon, 400-712, Korea

    Byung Hyune Choi

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  1. Jung Kyoung Choi
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Correspondence to Byung Hyune Choi.

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Choi, J.K., Kim, K.H., Park, H. et al. Granulocyte macrophage-colony stimulating factor shows anti-apoptotic activity in neural progenitor cells via JAK/STAT5-Bcl-2 pathway. Apoptosis 16, 127–134 (2011). https://doi.org/10.1007/s10495-010-0552-2

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