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Antiapoptotic Effect of Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Cyclic AMP on Human Neutrophils: Protein Synthesis-Dependent and Protein Synthesis-Independent Mechanisms and the Role of the Janus Kinase-STAT Pathway

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Abstract

Spontaneous neutrophil apoptosis during culture was delayed by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or dibutyryl-cyclic adenosine monophosphate (cAMP), whereas apoptosis was accelerated by cycloheximide or actinomycin D. G-CSF-mediated antiapoptosis was completely abolished by cycloheximide or actinomycin D, whereas GM-CSF-mediated antiapoptosis was not completely abolished by these inhibitors. Antiapoptosis induced by dibutyryl-cAMP was highly resistant to cycloheximide, and that induced by benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone was unaffected by cycloheximide. G-CSF- and GM-CSF-mediated antiapoptosis and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5 were inhibited by AG490, an inhibitor of Janus kinase.The level of Mcl-1 protein was not associated with neutrophil apoptosis. The results suggest that (a) neutrophil survival in the resting state is primarily regulated by the constitutive synthesis of antiapoptotic proteins; (b) the prevention of spontaneous apoptosis is mediated through the protein synthesis-dependent and/or protein synthesis-independent mechanisms according to the stimuli used; and (c) the Janus kinase-STAT pathway is involved in G-CSF- and GM-CSF-mediated antiapoptosis.

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References

  1. Suzuki K, Hasegawa T, Sakamoto C, et al. Cleavage of mitogen-activated protein kinases in human neutrophils undergoing apoptosis: role in decreased responsiveness to inflammatory cytokines.J Immunol. 2001;166:1185–1192.

    Article  CAS  PubMed  Google Scholar 

  2. Brach MA, de Vos S, Gruss HJ, Herrmann F. Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death.Blood. 1992;80:2920–2924.

    PubMed  CAS  Google Scholar 

  3. Takeda Y, Watanabe H, Yonehara S, et al. Rapid acceleration of neutrophil apoptosis by tumor necrosis factor-α.Int Immunol. 1993;5:691–694.

    Article  CAS  PubMed  Google Scholar 

  4. Parvathenani LK, Buescher ES, Chacon-Cruz E, et al. Type I cAMP-dependent protein kinase delays apoptosis in human neutrophils at a site upstream of caspase-3.J Biol Chem. 1998;273:6736–6743.

    Article  CAS  PubMed  Google Scholar 

  5. Moulding DA, Quayle JA, Hart A, et al. Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival.Blood. 1998;92:2495–2502.

    PubMed  CAS  Google Scholar 

  6. Chuang PI, Yee E, Karsan A, et al. A1 is a constitutive and inducible Bcl-2 homologue in mature human neutrophils.Biochem Biophys Res Commun. 1998;249:361–365.

    Article  CAS  PubMed  Google Scholar 

  7. Dibbert B, Weber M, Nikolaizik WH, et al. Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation.Proc Natl Acad Sci USA. 1999;96:13330–13335.

    Article  CAS  PubMed  Google Scholar 

  8. Leuenroth SJ, Grutkoski PS, Ayala A, et al. The loss of Mcl-1 expression in human polymorphonuclear leukocytes promotes apoptosis.J Leukoc Biol. 2000;68:158–166.

    PubMed  CAS  Google Scholar 

  9. Moulding DA, Akgul C, Derouet M, et al. BCL-2 family expression in human neutrophils during delayed and accelerated apoptosis.J Leukoc Biol. 2001;70:783–792.

    PubMed  CAS  Google Scholar 

  10. Epling-Burnette PK, Zhong B, Bai F, et al. Cooperative regulation of Mcl-1 by Janus kinase/STAT and phosphatidylinositol 3-kinase contribute to granulocyte-macrophage colony-stimulating factor-delayed apoptosis in human neutrophils.J Immunol. 2001;166:7486–7495.

    Article  CAS  PubMed  Google Scholar 

  11. Weinmann P, Gaehtgens P, Walzog B. Bcl-X1- and Bax-α-mediated regulation of apoptosis of human neutrophils via caspase-3.Blood. 1999;93:3106–3115.

    PubMed  CAS  Google Scholar 

  12. Maianski NA, Mul FPJ, van Buul JD, et al. Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils.Blood. 2002;99:672–679.

    Article  CAS  PubMed  Google Scholar 

  13. Wei S, Liu JH, Epling-Burnette PK, et al. Critical role of Lyn kinase in inhibition of neutrophil apoptosis by granulocyte-macrophage colony-stimulating factor.J Immunol. 1996;157:5155–5162.

    PubMed  CAS  Google Scholar 

  14. Klein JB, Rane MJ, Scherzer JA, et al. Granulocyte-macrophage colony-stimulating factor delays neutrophil constitutive apoptosis through phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways.J Immunol. 2000;164:4286–4291.

    Article  CAS  PubMed  Google Scholar 

  15. Takahashi M, Kitagawa S, Masuyama J, et al. Human monocyte-endothelial cell interaction induces synthesis of granulocyte-macrophage colony-stimulating factor.Circulation. 1996;93:1185–1193.

    Article  CAS  PubMed  Google Scholar 

  16. Kitagawa S, Ohta M, Nojiri H, et al. Functional maturation of membrane potential changes and superoxide-producing capacity during differentiation of human granulocytes.J Clin Invest. 1984;73:1062–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Reischl U, Linde H, Metz M, et al. Rapid identification of methi-cillin-resistantStaphylococcus aureus and simultaneous species confirmation using real-time fluorescence PCR.J Clin Microbiol. 2000;38:2429–2433.

    PubMed  PubMed Central  CAS  Google Scholar 

  18. Whyte MKB, Savill J, Meagher LC, et al. Coupling of neutrophil apoptosis to recognition by macrophages: coordinated acceleration by protein synthesis inhibitors.J Leukoc Biol. 1997;62:195–202.

    Article  CAS  PubMed  Google Scholar 

  19. Sakahira H, Enari M, Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis.Nature. 1998;391:96–99.

    Article  CAS  PubMed  Google Scholar 

  20. Yamashita K, Takahashi A, Kobayashi S, et al. Caspases mediate tumor necrosis factor-α-induced neutrophil apoptosis and down-regulation of reactive oxygen production.Blood. 1999;93:674–685.

    CAS  PubMed  Google Scholar 

  21. Chakraborty A, Tweardy DJ. Granulocyte colony-stimulating factor activates a 72-kDa isoform of STAT3 in human neutrophils.J Leukoc Biol. 1998;64:675–680.

    Article  CAS  PubMed  Google Scholar 

  22. Levitzki A. Protein tyrosine kinase inhibitors as novel therapeutic agents.Pharmacol Ther. 1999;82:231–239.

    Article  CAS  PubMed  Google Scholar 

  23. Al-Shami A, Mahanna W, Naccache PH. Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils: selective activation of Jak2, Stat3, and Stat5B.J Biol Chem. 1998;273:1058–1063.

    Article  CAS  PubMed  Google Scholar 

  24. Suzuki K, Hino M, Hato F, et al. Cytokine-specific activation of distinct mitogen-activated protein kinase subtype cascades in human neutrophils stimulated by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-α.Blood. 1999;93:341–349.

    CAS  PubMed  Google Scholar 

  25. Ohta K, Iwai K, Kasahara Y, et al. Immunoblot analysis of cellular expression of Bcl-2 family proteins, Bcl-2, Bax, Bcl-X and Mcl-1, in human peripheral blood and lymphoid tissues.Int Immunol. 1995;7:1817–1825.

    Article  CAS  PubMed  Google Scholar 

  26. Krajewski S, Bodrug S, Krajewska M, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues: differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo.Am J Pathol. 1995;146:1309–1319.

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Iwai K, Miyawaki T, Takizawa T, et al. Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils.Blood. 1994;84:1201–1208.

    PubMed  CAS  Google Scholar 

  28. Pongracz J, Webb P, Wang K, et al. Spontaneous neutrophil apoptosis involves caspase 3-mediated activation of protein kinase C-δ.J Biol Chem. 1999;274:37329–37334.

    Article  CAS  PubMed  Google Scholar 

  29. Kieslinger M, Woldman I, Moriggl R, et al. Antiapoptotic activity ofStat5 required during terminal stages of myeloid differentiation.Genes Dev. 2000;14:232–244.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Caldenhoven E, van Dijk TB, Solari R, et al. STAT3β, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription.J Biol Chem. 1996;271:13221–13227.

    Article  CAS  PubMed  Google Scholar 

  31. Sasse J, Hemmann U, Schwartz C, et al. Mutational analysis of acute-phase response factor/Stat3 activation and dimerization.Mol Cell Biol. 1997;17:4677–4686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schaefer TS, Sanders LK, Nathans D. Cooperative transcriptional activity of Jun and Stat3β, a short form of Stat3.Proc Natl Acad Sci USA. 1995;92:9097–9101.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departments of aPhysiology, Osaka City University Medical School, 545-8585, Asahi-machi, Abeno-ku, Osaka, Japan

    Chikahiko Sakamoto, Kenichi Suzuki, Fumihiko Hato, Mika Akahori, Taro Hasegawa & Seiichi Kitagawa

  2. Clinical Hematology, Osaka City University Medical School, Osaka, Japan

    Masayuki Hino

Authors
  1. Chikahiko Sakamoto
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  2. Kenichi Suzuki
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  3. Fumihiko Hato
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  4. Mika Akahori
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  5. Taro Hasegawa
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  6. Masayuki Hino
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  7. Seiichi Kitagawa
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Correspondence to Seiichi Kitagawa.

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Sakamoto, C., Suzuki, K., Hato, F. et al. Antiapoptotic Effect of Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Cyclic AMP on Human Neutrophils: Protein Synthesis-Dependent and Protein Synthesis-Independent Mechanisms and the Role of the Janus Kinase-STAT Pathway. Int J Hematol 77, 60–70 (2003). https://doi.org/10.1007/BF02982604

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  • DOI: https://doi.org/10.1007/BF02982604

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