Skip to main content
SpringerLink
Log in

Regulation of Neutrophil Functions by Proinflammatory Cytokines

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Various functions of mature human neutrophils are activated or potentiated by hematopoietic growth factors or proinflammatory cytokines such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin 1β. The major signaling pathways activated in human neutrophils stimulated by proinflammatory cytokines include mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, phosphatidylinositol 3-kinase, and nuclear factor κB. These signaling pathways are involved in cytokine-mediated regulation of neutrophil functions in a cytokine-specific manner.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kitagawa S, Yuo A, Souza LM, Saito M, Miura Y, Takaku F. Recombinant human granulocyte colony-stimulating factor enhances superoxide release in human granulocytes stimulated by the chemotactic peptide. Biochem Biophys Res Commun. 1987;144: 1143–1146.

    Article  CAS  PubMed  Google Scholar 

  2. Yuo A, Kitagawa S, Ohsaka A, et al. Recombinant human granulocyte colony-stimulating factor as an activator of human granulocytes: potentiation of responses triggered by receptor-mediated agonists and stimulation of C3bi receptor expression and adherence. Blood. 1989;74:2144–2149.

    PubMed  CAS  Google Scholar 

  3. Yuo A, Kitagawa S, Suzuki I, et al. Tumor necrosis factor as an activator of human granulocytes: potentiation of the metabolisms triggered by the Ca2+-mobilizing agonists. J Immunol. 1989;142: 1678–1684.

    PubMed  CAS  Google Scholar 

  4. Suzuki K, Hino M, Hato F, Tatsumi N, Kitagawa S. 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.

    PubMed  CAS  Google Scholar 

  5. 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 

  6. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4:181–189.

    Article  CAS  PubMed  Google Scholar 

  7. Hoyal CR, Gutierrez A, Young BM, et al. Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase. Proc Natl Acad Sci U S A. 2003;100:5130–5135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Suzuki K, Hino M, Kutsuna H, et al. Selective activation of p38 mitogen-activated protein kinase cascade in human neutrophils stimulated by IL-1β. J Immunol. 2001;167:5940–5947.

    Article  CAS  PubMed  Google Scholar 

  9. Dang PM, Stensballe A, Boussetta T, et al. A specific p47phox-serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Invest. 2006;116:2033–2043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhu QS, Xia L, Mills GB, Lowell CA, Touw IP, Corey SJ. G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth. Blood. 2006;107:1847–1856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hermans MH, Antonissen C, Ward AC, Mayen AE, Ploemacher RE, Touw IP. Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. J Exp Med. 1999;189: 683–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kamata N, Kutsuna H, Hato F, et al. Activation of human neutrophils by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-a: the role of phosphatidylinositol 3-kinase. Int J Hematol. 2004;80: 421–427.

    Article  CAS  PubMed  Google Scholar 

  13. Chen Q, Powell DW, Rane MJ, et al. Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. J Immunol. 2003;170:5302–5308.

    Article  CAS  PubMed  Google Scholar 

  14. Han H, Fuortes M, Nathan C. Critical role of the carboxyl terminus of proline-rich tyrosine kinase (Pyk2) in the activation of human neutrophils by tumor necrosis factor: separation of signals for the respiratory burst and degranulation. J Exp Med. 2003;197:63–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fuortes M, Melchior M, Han H, Lyon GJ, Nathan C. Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF. J Clin Invest. 1999;104:327–335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sims JE, Gayle MA, Slack JL, et al. Interleukin 1 signaling occurs exclusively via the type I receptor. Proc Natl Acad Sci U S A. 1993;90:6155–6159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Takahashi T, Hato F, Yamane T, et al. Activation of human neutrophil by cytokine-activated endothelial cells. Circ Res. 2001;88: 422–429.

    Article  CAS  PubMed  Google Scholar 

  18. Bourke E, Cassetti A, Villa A, Fadlon E, Colotta F, Mantovani A. IL-1β scavenging by the type II IL-1 decoy receptor in human neutrophils. J Immunol. 2003;170:5999–6005.

    Article  CAS  PubMed  Google Scholar 

  19. Kutsuna H, Suzuki K, Kamata N, et al. Actin reorganization and morphological changes in human neutrophils stimulated by TNF, GM-CSF and G-CSF: role of mitogen-activated protein kinases. Am J Physiol Cell Physiol. 2004;286:C55-C64.

    Article  CAS  PubMed  Google Scholar 

  20. Vollmer KL, Alberts JS, Carper HT, Mandell GL. Tumor necrosis factor-a decreases neutrophil chemotaxis toN-formyl-l-methionyl-l-leucyl-l-phenylalanine:analysis of single cell movement. J LeukocBiol. 1992;52:630–636.

    Article  CAS  Google Scholar 

  21. Peppelenbosch M, Boone E, Jones GE, et al. Multiple signal transduction pathways regulate TNF-induced actin reorganization in macrophages: inhibition of Cdc-42-mediated filopodium formation by TNF. J Immunol. 1999;162:837–845.

    PubMed  CAS  Google Scholar 

  22. Nakamae-Akahori M, Kato T, Masuda S, et al. Enhanced neutrophil motility by granulocyte colony-stimulating factor: the role of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. Immunology. In press.

  23. Vial E, Pouyssegur J. Regulation of tumor cell motility by ERK mitogen-activated protein kinases. Ann N Y Acad Sci. 2004;1030:208–218.

    Article  CAS  Google Scholar 

  24. Alblas J, Ulfman L, Hordijk P, Koenderman L. Activation of RhoA and ROCK are essential for detachment of migrating leukocytes. Mol Biol Cell. 2001;12:2137–2145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sakamoto C, Suzuki K, Hato F, et al. Anti-apoptotic 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 role of Janus kinase-STAT pathway. Int J Hematol. 2003;77:60–70.

    Article  CAS  PubMed  Google Scholar 

  26. 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 

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

    Article  CAS  PubMed  Google Scholar 

  28. Cowburn AS, Cadwallader KA, Reed BJ, Farahi N, Chilvers ER. Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood. 2002;100:2607–2616.

    Article  CAS  PubMed  Google Scholar 

  29. Hasegawa T, Suzuki K, Sakamoto C, et al. Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia. Blood. 2003;101:1164–1171.

    Article  CAS  PubMed  Google Scholar 

  30. Maianski NA, Roos D, Kuijpers TW. Bid truncation, Bid/Bax targeting to the mitochondria, and caspase activation associated with neutrophil apoptosis are inhibited by granulocyte colony-stimulating factor. J Immunol. 2004;172:7024–7030.

    Article  CAS  PubMed  Google Scholar 

  31. Altznauer F, Martinelli S, Yousefi S, et al. Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J Exp Med. 2004;199:1343–1354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sakamoto E, Hato F, Kato T, et al. Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2. J Leukoc Biol. 2005;78:301–309.

    Article  CAS  PubMed  Google Scholar 

  33. Kato T, Sakamoto E, Kutsuna H, Kimura-Eto A, Hato F, Kitagawa S. Proteolytic conversion of STAT3α to STAT3γ in human neutrophils:role of granule-derived serine proteases. J Biol Chem. 2004;279:31076–31080.

    Article  CAS  PubMed  Google Scholar 

  34. Wang K, Scheel-Toellner D, Wong SH, et al. Inhibition of neutrophil apoptosis by type 1 IFN depends on cross-talk between phosphoinositol 3-kinase, protein kinase C-δ, and NF-κB signaling pathways. J Immunol. 2003;171:1035–1041.

    Article  CAS  PubMed  Google Scholar 

  35. Kilpatrick LE, Sun S, Korchak HM. Selective regulation by δ-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils. Am J Physiol Cell Physiol. 2004;287:C633-C642.

    Article  CAS  PubMed  Google Scholar 

  36. Kobayashi S, Yamashita K, Takeoka T, et al. Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia. J Biol Chem. 2002;277:33968–33977.

    Article  CAS  PubMed  Google Scholar 

  37. Nishiki S, Hato F, Kamata N, et al. Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-α production. Am J Physiol Cell Physiol. 2004;286:C1302-C1311.

    Article  CAS  PubMed  Google Scholar 

  38. Görgen I, Hartung T, Leist M, et al. Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-α. J Immunol. 1992;149:918–924.

    PubMed  Google Scholar 

  39. Hartung T, Döcke WD, Gantner F, et al. Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood. 1995;85:2482–2489.

    PubMed  CAS  Google Scholar 

  40. Joshi SS, Lynch JC, Pavletic SZ, et al. Decreased immune functions of blood cells following mobilization with granulocyte colony-stimulating factor: association with donor characteristics. Blood. 2001;98:1963–1970.

    Article  CAS  PubMed  Google Scholar 

  41. Volpi I, Perruccio K, Tosti A, et al. Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype-mis-matched hematopoietic transplants. Blood. 2001;97:2514–2521.

    Article  CAS  PubMed  Google Scholar 

  42. Ringdén O, Remberger M, Runde V, et al. Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation. Blood. 1999;94:455–464.

    PubMed  Google Scholar 

  43. Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science. 2003;300:1524–1525.

    Article  CAS  PubMed  Google Scholar 

  44. Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science. 2003;301:640–643.

    Article  CAS  PubMed  Google Scholar 

  45. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791–2808.

    PubMed  CAS  Google Scholar 

  46. Ohsaka A, Kitagawa S, Sakamoto S, et al. In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma. Blood. 1989;74:2743–2748.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Osaka City University Graduate School of Medicine, 545-8585, Asahi-machi, Abeno-ku Osaka, Japan

    Takayuki Kato & Seiichi Kitagawa

Authors
  1. Takayuki Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seiichi Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seiichi Kitagawa.

About this article

Cite this article

Kato, T., Kitagawa, S. Regulation of Neutrophil Functions by Proinflammatory Cytokines. Int J Hematol 84, 205–209 (2006). https://doi.org/10.1532/IJH97.06141

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.06141

Key words

Search

Navigation