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Role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and nuclear transcription factor kappa β (NF-kβ) on neutrophil phagocytic process of Candida albicans

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Abstract

In humans, Candida albicans is the microorganism most frequently associated with fungal infections. Alterations in the balance between the host and this commensal pathogen, turns into a parasitic relationship which results in the development of invasive infections. Neutrophils via chemotaxis, phagocytosis, and microbicide capacity can eradicate this pathogen. Taken together, the aim of this work was to study the possible role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and the nuclear transcription factor kappa β (NF-kβ) on the phagocytic process of neutrophils. The chemotactic capacity of neutrophils and their ability to phagocytose and to destroy C. albicans in absence and presence of 1, 10, or 100 μM of wortmannin (a PI3K inhibitor); 10, 25, or 50 μM of Bay 11-7082 (a NF-kβ inhibitor) or 1, 5 or 10 μM of PD 98,059 (an ERK inhibitor) were determined. Our results show that fMLP-induced chemotaxis needs the participation of PI3K and NF-kβ. In contrast, ERK seems not to be involved. On the other hand, the inhibition of NF-kβ and ERK decreased neutrophil phagocytosis and microbicide capacity against C. albicans. However, both the phagocytic and candicide capacities were PI3K independent.

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References

  1. Garber G (2001) An overview of fungal infections. Drugs 61:1–12

    Article  PubMed  Google Scholar 

  2. Romani L (2004) Immunity to fungal infections. Nat Rev Immunol 4:1–23

    Article  PubMed  Google Scholar 

  3. Marr KA, Patterson T, Denning D (2002) Aspergillosis: parthenogenesis, clinical manifestations, and therapy. Infect Dis Clin North Am 16:875–894

    Article  PubMed  Google Scholar 

  4. Bellochio S, Moretti S, Perruccio K, Fallarino F, Bozza S, Montagnoli C, Mosci P, Lipford GB, Pitzurra L, Romani L (2004) TLRs govern neutrophil activity in Aspergillosis. J Immunol 173:7406–7415

    Google Scholar 

  5. Greenberg S, Grinstein S (2002) Phagocytosis and innate immunity. Curr Opin Immunol 14:136–145

    Article  CAS  PubMed  Google Scholar 

  6. Medzhitov R, Preston-Hurlburt P, Janeway CA (1997) A human homologue of the Drosphilia Toll protein signals activation of adaptive immunity. Nature. 388:394–397

    Article  CAS  PubMed  Google Scholar 

  7. Netea MG, Van der Graaf CA, Vonk AG, Verschueren I, Van der Meer JW, Kullberg BJ (2002) The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infec Dis 185:1483–1489

    Article  CAS  Google Scholar 

  8. Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102:2660–2669

    Article  CAS  PubMed  Google Scholar 

  9. Beutler B (2000) Tlr4: central component of the sole mammalian LPS sensor. Curr Opin Immunol 12:20–26

    Article  CAS  PubMed  Google Scholar 

  10. Francois S, El Benna J, Dang PM, Pedruzzi E, Gougerot-Pocidalo MA, Elbim C (2005) Inhibition of neutrophil apoptosis by TLR agonists in whole blood: involvement of the phosphoinositide 3-kinase/Akt and NF-kappaB signaling pathways, leading to increased levels of Mcl-1, A1, and phosphorylated Bad. J Immunol 174:3633–3642

    CAS  PubMed  Google Scholar 

  11. Yum HK, Arcaroli J, Kupfner J, Shenkar R, Penninger JM, Sasaki T, Yang KY, Park JS, Abraham E (2001) Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J Immunol 167:6601–6608

    CAS  PubMed  Google Scholar 

  12. Strassheim D, Asehnoune K, Park JS, Kim JY, He Q, Richter D, Kuhn K, Mitra S, Abraham E (2004) Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils. J Immunol 172:5727–5733

    CAS  PubMed  Google Scholar 

  13. Asea A (2003) Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 9:25–33

    PubMed  Google Scholar 

  14. Ortega E, Hinchado MD, Martín-Cordero L, Asea A (2009) The effect of stress-inducible extracelular Hsp72 on human neutrophils chemotaxis: the role during acute intense exercise. Stress 12:240–249

    Article  CAS  PubMed  Google Scholar 

  15. Fidel PL (2002) Distinct protective host defenses against oral and vaginal candidiasis. Med Mycol 40:359–375

    Article  PubMed  Google Scholar 

  16. Roeder A, Kirschning CJ, Rupec RA, Schaller M, Korting HC (2004) Toll like receptors and innate antifungal responses. Trends Microbiol 12:44–49

    Article  CAS  PubMed  Google Scholar 

  17. Farnell MB, He H, Genovese K, Kogut MH (2003) Pharmacological analysis of signal transduction pathways required for oxidative burst in chicken heterophils stimulated by a Toll-like receptor 2 agonist. Int Immunopharmacol. 3:1677–1684

    Article  CAS  PubMed  Google Scholar 

  18. Ortega E, Forner MA, Barriga C (1997) Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol 498:729–734

    CAS  PubMed  Google Scholar 

  19. Coelho AL, De Freitas MS, Mariano-Oliveira A, Oliveira-Carvalho AL, Zingali RB, Barja-Fidalgo C (2001) Interaction of disintegrins with human neutrophils induces cytoskeleton reorganization, focal adhesion kinase activation, and extracellular-regulated kinase-2 nuclear translocation, interfering with the chemotactic fuction. FASEB J 15:1643–1645

    CAS  PubMed  Google Scholar 

  20. Ortega E, Collazos ME, Maynar M, Barriga C, De la Fuente M (1993) Stimulation of the phagocytic function of neutrophils in sedentary men alter acute moderate exercise. Eur J Appl Physiol Occup Physiol 66:60–64

    Article  CAS  PubMed  Google Scholar 

  21. Ortega E, Marchena JM, García JJ, Barriga C (2005) Norepinephrine as mediator in the stimulation of phagocytosis induced by moderate exercise. Eur J Appl Physiol 93:714–718

    Article  CAS  PubMed  Google Scholar 

  22. Giraldo E, Hinchado MD, Garcia JJ, Ortega E (2008) Influence of gender and oral contraceptives intake on innate and inflammatory response. Role of neuroendocrine factors. Mol Cell Biochem 313:147–153

    Article  CAS  PubMed  Google Scholar 

  23. Nakamae-Akahori M, Kato T, Masuda S, Sakamoto E, Kutsuna H, Hato F, Nishizawa Y, Hino M, Kitagawa S (2006) Enhanced neutrophil motility by granulocyte colony-stimulating factor: the role of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. Immunology 119:393–403

    Article  CAS  PubMed  Google Scholar 

  24. Firtel RA, Chung CY (2000) The molecular genetics of chemotaxis: sensing and responding to chemoattractant gradients. Bioessays 22:603–615

    Article  CAS  PubMed  Google Scholar 

  25. Stephens L, Ellson C, Hawkins P (2002) Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 14:203–213

    Article  CAS  PubMed  Google Scholar 

  26. Wymann MP, Sozzani S, Altruda F, Mantovani A, Hirch E (2000) Lipids on the move: phosphoinositide 3-kinases in leukocyte function. Immunol Today 21:260–264

    Article  CAS  PubMed  Google Scholar 

  27. Cloutier A, Ear T, Blais-Charron E, Dubois CM, McDonald PP (2007) Differential involvement of NF-kappaB and MAP kinase pathways in the generation of inflammatory cytokines by human neutrophils. J Leukoc Biol 81:567–577

    Article  CAS  PubMed  Google Scholar 

  28. Pierce JW, Schvenleber R, Jesmok G, Best J, Moore SA, Collins T (1997) Novel inhibitors of cytokine-induced IkBα phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J Biol Chem 272:21096–21103

    Article  CAS  PubMed  Google Scholar 

  29. Downey GP, Butler JR, Tapper H, Fialkow L, Saltiel AR, Rubin BB, Grinstein S (1998) Importance of MEK in neutrophil microbicidal responsiveness. J Immunol 160:434–443

    CAS  PubMed  Google Scholar 

  30. Zu YL, Qi J, Gilchrist A, Fernandez GA, Vazquez-Abad D, Kreutzer DL, Huang CK, Sha’afi RI (1998) p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation. J Immunol 160:1982–1989

    CAS  PubMed  Google Scholar 

  31. Kanakaraj P, Duckworth B, Azzoni L, Kamoun M, Cantley LC, Perussia B (1994) Phosphatidylinositol-3 kinase activation induced upon FcgRIIIA-ligand interaction. J Exp Med 179:551–558

    Article  CAS  PubMed  Google Scholar 

  32. Ninomiya N, Hazeki K, Fukui Y, Seya T, Okada T, Hazeki O, Ui M (1994) Involvement of phosphatidylinositol 3-kinase in Fc gamma receptor signaling. J Biol Chem 269:22732–22737

    CAS  PubMed  Google Scholar 

  33. Dewitt S, Hallett MB (2002) Cytosolic free Ca(2+) changes and calpain activation are required for beta integrin-accelerated phagocytosis by human neutrophils. J Cell Biol 159:181–189

    Article  CAS  PubMed  Google Scholar 

  34. Moraes TJ, Downey GP (2003) Neutrophil cell signaling in infection: role of phosphatidylinositide 3-kinase. Microbes Infect 5:1293–1298

    Article  CAS  PubMed  Google Scholar 

  35. Hii CST, Stacey K, Moghaddami N, Murray AW, Ferrante A (1999) Role of the extracellular signal-regulated kinase cascade in human neutrophil killing of Staphylococcus aureus and Candida albicans and migration. Infect Immun 67:1297–1302

    CAS  PubMed  Google Scholar 

  36. Meyer H, Goettlicher S, Mendling W (2006) Stress as a cause of chronic recurrent vulvovaginal candidosis and the effectiveness of the conventional antimycotic therapy. Mycoses 49:2002–2209

    Article  Google Scholar 

  37. Giraldo E, Garcia JJ, Hinchado MD, Ortega E (2009) Exercise intensity-dependent changes in the inflammatory response in sedentary women: role of neuroendocrine parameters in the neutrophil phagocytic process and the pro-/anti-inflammatory cytokine balance. Neuroimmunomodulation 16:237–244

    Article  CAS  PubMed  Google Scholar 

  38. Murciano C, Villamón E, Yañez A, O’Connor JE, Gozalbo D, Gil ML (2006) Imparied immune response to candida albicans in aged mice. J Med Microbiol 55:1649–1656

    Article  CAS  PubMed  Google Scholar 

  39. Polak A (2003) Antifungal agents: advances and problems, Chapter 4. In Jnucker E (ed). Birkhauser Verlag, Basel, pp 59–190

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Acknowledgments

This work was supported by grants of II (2PR04A076) and III (PRI06A172) and a fellowship from Consejeria de Educacion, Ciencia y Tecnologia of the Junta de Extremadura, and Fondo Social Europeo, as well as by a fellow from “Fundación Valhondo”.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Sciences, University of Extremadura, 06071, Badajoz, Spain

    E. Giraldo, L. Martin-Cordero, M. D. Hinchado, J. J. Garcia & E. Ortega

  2. Departamento de Fisiología, Facultad de Ciencias, Universidad de Extremadura, 06071, Badajoz, España

    E. Ortega

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  1. E. Giraldo
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  2. L. Martin-Cordero
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  3. M. D. Hinchado
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Correspondence to E. Ortega.

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Giraldo, E., Martin-Cordero, L., Hinchado, M.D. et al. Role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and nuclear transcription factor kappa β (NF-kβ) on neutrophil phagocytic process of Candida albicans . Mol Cell Biochem 333, 115–120 (2010). https://doi.org/10.1007/s11010-009-0211-5

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