Skip to main content

Advertisement

SpringerLink
Log in

Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

The injured skin produces a number of mediators that directly or indirectly modulate cell chemotaxis, migration, proliferation, and angiogenesis. Components of the kinin pathway including the kinin B1 receptor (B1R) have been found to occur in the human skin, but information about its role on keratinocyte biology is still scarce. Our aim was to determine whether stimulation of B1R causes the secretion of IL-4 and/or VEGF from human keratinocytes and to evaluate the role of the B1R agonist Lys-des[Arg9]bradykinin and IL-4 on various stages of angiogenesis, such as cell migration, proliferation, and release of metalloproteases. By using ELISA and Western blotting, we showed that HaCaT keratinocytes stimulated with the B1R agonist release IL-4 and VEGF. Stimulation of B1R also caused transient c-JunN-terminal kinase phosphorylation and JunB nuclear translocation, transcription factor that regulates IL-4 expression. The 3D-angiogenesis assay, performed on spheroids of EA.hy923 endothelial cells embedded in a collagen matrix, showed that their cumulative sprout area increased significantly following stimulation with either IL-4 or B1R agonist. Furthermore, these ligands produced significant endothelial cell migration and release of metalloproteases 2 and 9, but did not increase endothelial cell proliferation as measured by 5-bromo-2′-deoxyuridine incorporation. Our results provide experimental evidence that establishes IL-4 and B1R agonist as important angiogenic factors of relevance for skin repair.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Bakiri L, Lallemand D, Bossy-Wetzel E, Yaniv M (2000) Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression. EMBO J 19(9):2056–2068

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Benelli R, Lorusso G, Albini A, Noonan DM (2006) Cytokines and chemokines as regulators of angiogenesis in health and disease. Curr Pharm Des 12(24):3101–3115

    Article  CAS  PubMed  Google Scholar 

  3. Bhogal RK, Bona CA (2008) Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13. Int Rev Immunol 27(6):472–496

    Article  CAS  PubMed  Google Scholar 

  4. Bhoola KD, Figueroa CD, Worthy K (1992) Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 44(1):1–80

    CAS  PubMed  Google Scholar 

  5. Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106(3):761–771

    Article  CAS  PubMed  Google Scholar 

  6. Brandt EB, Sivaprasad U (2011) Th2 Cytokines and atopic dermatitis. J Clin Cell Immunol 2(3):110. doi:10.4172/2155-9899.1000110

    Article  PubMed Central  PubMed  Google Scholar 

  7. Brechter AB, Persson E, Lundgren I, Lerner UH (2008) Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-κB and MAP kinases. Bone 43(1):72–83

    Article  CAS  PubMed  Google Scholar 

  8. Bryborn M, Adner M, Cardell LO (2004) Interleukin-4 increases murine airway response to kinins, via up-regulation of bradykinin B1-receptors and altered signalling along mitogen-activated protein kinase pathways. Clin Exp Allergy 34(8):1291–1298

    Article  CAS  PubMed  Google Scholar 

  9. Cai Y, Huang L, Leung T, Burd A (2014) A study of the immune properties of human umbilical cord lining epithelial cells. Cytotherapy 16(5):631–639

    Article  CAS  PubMed  Google Scholar 

  10. Calautti E, Li J, Saoncella S, Brissette JL, Goetinck PF (2005) Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem 280(38):32856–32865

    Article  CAS  PubMed  Google Scholar 

  11. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75(1):50–83

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Chamberlain CS, Leiferman EM, Frisch KE, Wang S, Yang X, Brickson SL et al (2011) The influence of interleukin-4 on ligament healing. Wound Repair Regen 19(3):426–435

    Article  PubMed Central  PubMed  Google Scholar 

  13. Christiansen SC, Eddleston J, Woessner KM, Chambers SS, Ye R, Pan ZK et al (2002) Up-regulation of functional kinin B1 receptors in allergic airway inflammation. J Immunol 169(4):2054–2060

    Article  CAS  PubMed  Google Scholar 

  14. Costa R, Manjavachi MN, Motta EM, Marotta DM, Juliano L, Torres HA et al (2010) The role of kinin B1 and B2 receptors in the scratching behaviour induced by proteinase-activated receptor-2 agonists in mice. Br J Pharmacol 159(4):888–897

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Ehrenfeld P, Millan C, Matus CE, Figueroa J, Burgos R, Nualart F et al (2006) Activation of kinin B1 receptors induces chemotaxis of human neutrophils. J Leukoc Biol 80(1):117–124

    Article  CAS  PubMed  Google Scholar 

  16. Ehrenfeld P, Matus CE, Pavicic F, Toledo C, Nualart F, Gonzalez CB et al (2009) Kinin B1 receptor activation turns on exocytosis of matrix metalloprotease-9 and myeloperoxidase in human neutrophils: involvement of mitogen-activated protein kinase family. J Leukoc Biol 86(5):1179–1189

    Article  CAS  PubMed  Google Scholar 

  17. Ehrenfeld P, Conejeros I, Pavicic MF, Matus CE, Gonzalez CB, Quest AF et al (2011) Activation of kinin B1 receptor increases the release of metalloproteases-2 and -9 from both estrogen-sensitive and -insensitive breast cancer cells. Cancer Lett 301(1):106–118

    Article  CAS  PubMed  Google Scholar 

  18. Emanueli C, Minasi A, Zacheo A, Chao J, Chao L, Salis MB et al (2001) Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 103(1):125–132

    Article  CAS  PubMed  Google Scholar 

  19. Emanueli C, Salis MB, Stacca T, Pintus G, Kirchmair R, Isner JM et al (2002) Targeting kinin B1 receptor for therapeutic neovascularization. Circulation 105(3):360–366

    Article  CAS  PubMed  Google Scholar 

  20. Enquist J, Skröder C, Whistler JL, Leeb-Lundberg LMF (2007) Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis. Mol Pharmacol 71(2):494–507

    Article  CAS  PubMed  Google Scholar 

  21. Esche C, de Benedetto A, Beck LA (2004) Keratinocytes in atopic dermatitis: inflammatory signals. Curr Allergy Asthma Rep 4(4):276–284

    Article  PubMed  Google Scholar 

  22. Figueroa CD, Matus CE, Pavicic F, Sarmiento J, Hidalgo MA, Burgos RA et al (2015) Kinin B1 receptor regulates interactions between neutrophils and endothelial cells by modulating the levels of Mac-1, LFA-1 and intercellular adhesion molecule-1. Innate Immun 21(3):289–304

    Article  CAS  PubMed  Google Scholar 

  23. Fukushi J, Morisaki T, Shono T, Nishie A, Torisu H, Ono M et al (1998) Novel biological function of interleukin-4: formation of tube-like structures by vascular endothelial cells in vitro and angiogenesis in vivo. Biochem Biophys Res Commun 250(2):444–448

    Article  CAS  PubMed  Google Scholar 

  24. Fukushi J, Ono M, Morikawa W, Iwamoto Y, Kuwano M (2000) The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13. J Immunol 165(5):2818–2823

    Article  CAS  PubMed  Google Scholar 

  25. Gulliver R, Baltic S, Misso NL, Bertram CM, Thompson PJ, Fogel-Petrovic M (2011) Lys-des[Arg9]-bradykinin alters migration and production of interleukin-12 in monocyte-derived dendritic cells. Am J Respir Cell Mol Biol 45(3):542–549

    Article  CAS  PubMed  Google Scholar 

  26. Hosogi M, Schmelz M, Miyachi Y, Ikoma A (2006) Bradykinin is a potent pruritogen in atopic dermatitis: a switch from pain to itch. Pain 126(1–3):16–23

    Article  CAS  PubMed  Google Scholar 

  27. Johansen C, Kragballe K, Henningsen J, Westergaard M, Kristiansen K, Iversen L (2003) 1alpha,25-dihydroxyvitamin D3 stimulates activator protein 1 DNA-binding activity by a phosphatidylinositol 3-kinase/Ras/MEK/extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1-dependent increase in c-Fos, Fra1, and c-Jun expression in human keratinocytes. J Invest Dermatol 120(4):561–570

    Article  CAS  PubMed  Google Scholar 

  28. Korff T, Augustin HG (1998) Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol 143(5):1341–1352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Korff T (2004) Three-dimensional in vitro angiogenesis assays. In: Augustin HG (ed) Methods in endothelial cell biology. Springer-Verlag, Berlin, pp 115–123

    Chapter  Google Scholar 

  30. Lang W, Wang H, Ding L, Xiao L (2004) Cooperation between PKC-alpha and PKC-epsilon in the regulation of JNK activation in human lung cancer cells. Cell Signal 16(4):457–467

    Article  CAS  PubMed  Google Scholar 

  31. Li B, Tournier C, Davis RJ, Flavell RA (1999) Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J 18(2):420–432

    Article  PubMed Central  PubMed  Google Scholar 

  32. Liang J, He Y, Ji W (2012) Bradykinin-evoked scratching responses in complete Freund’s adjuvant-inflamed skin through activation of B1 receptor. Exp Biol Med (Maywood) 237(3):318–326

    Article  CAS  Google Scholar 

  33. Linde N, Lederle W, Depner S, van Rooijen N, Gutschalk CM, Mueller MM (2012) Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. J Pathol 227(1):17–28

    Article  CAS  PubMed  Google Scholar 

  34. Lu DY, Leung YM, Huang SM, Wong KL (2010) Bradykinin-induced cell migration and COX-2 production mediated by the bradykinin B1 receptor in glioma cells. J Cell Biochem 110(1):141–150

    CAS  PubMed  Google Scholar 

  35. Luzina IG, Lockatell V, Lavania S, Pickering EM, Kang PH, Bashkatova YN et al (2012) Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma. Cytokine 58(1):20–26

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Marceau F, Hess JF, Bachvarov DR (1998) The B1 receptors for kinins. Pharmacol Rev 50(3):357–386

    CAS  PubMed  Google Scholar 

  37. Matsuda A, Fukuda S, Matsumoto K, Saito H (2008) Th1/Th2 Cytokines reciprocally regulate in vitro pulmonary angiogenesis via CXC chemokine synthesis. Am J Respir Cell Mol Biol 38(2):168–175

    Article  CAS  PubMed  Google Scholar 

  38. Matus CE, Ehrenfeld P, Pavicic F, Sarmiento JM, Astroza A, Sanchez T et al (2008) Activation of kinin B receptor triggers differentiation of cultured human keratinocytes. Br J Dermatol 159(4):792–803

    Article  CAS  PubMed  Google Scholar 

  39. Miura S, Matsuo Y, Saku K (2003) Transactivation of KDR/Flk-1 by the B2 receptor induces tube formation in human coronary endothelial cells. Hypertension 41(5):1118–1123

    Article  CAS  PubMed  Google Scholar 

  40. Morbidelli L, Parenti A, Giovannelli L, Granger HJ, Ledda F, Ziche M (1998) B1 Receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF-2 effects. Br J Pharmacol 124(6):1286–1292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Morissette G, Sabourin T, Adam A, Marceau F (2006) Inhibition of human and rabbit arterial smooth muscle cell migration mediated by the kinin B1 receptor: role of receptor density and released mediators. Can J Physiol Pharmacol 84(11):1107–1119

    Article  CAS  PubMed  Google Scholar 

  42. Narayanan K, Srinivas R, Peterson MC, Ramachandran A, Hao J, Thimmapaya B et al (2004) Transcriptional regulation of dentin matrix protein 1 by JunB and p300 during osteoblast differentiation. J Biol Chem 279(43):44294–44302

    Article  CAS  PubMed  Google Scholar 

  43. Oeseburg H, Iusuf D, van der Harst P, van Gilst WH, Henning RH, Roks AJ (2009) Bradykinin protects against oxidative stress-induced endothelial cell senescence. Hypertension 53(2):417–422

    Article  CAS  PubMed  Google Scholar 

  44. Paegelow I, Trzeczak S, Böckman S, Vietinghoff G (2002) Migratory responses of polymorphonuclear leukocytes to kinin peptides. Pharmacology 66(3):153–161

    Article  CAS  PubMed  Google Scholar 

  45. Parenti A, Morbidelli L, Ledda F, Granger HJ, Ziche M (2001) The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway. FASEB J 15(8):1487–1489

    CAS  PubMed  Google Scholar 

  46. Pietrovski EF, Paludo KS, Mendes DA, Guimarães Fde S, Veiga SS, Buchi Dde F et al (2011) B1 and B2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice. J Dermatol Sci 64(1):23–30

    Article  CAS  PubMed  Google Scholar 

  47. Postlethwaite AE, Seyer JM (1991) Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70–88 and 89–122. J Clin Invest 87(6):2147–2152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Rincon M, Derijard B, Chow CW, Davis RJ, Flavell RA (1997) Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector Th1 and Th2 cells. Genes Funct 1(1):51–68

    Article  CAS  PubMed  Google Scholar 

  49. Salmon-Ehr V, Ramont L, Godeau G, Birembaut P, Guenounou M, Bernard P et al (2000) Implication of interleukin-4 in wound healing. Lab Invest 80(8):1337–1343

    Article  CAS  PubMed  Google Scholar 

  50. Sanchez de Miguel L, Neysari S, Jakob S, Petrimpol M, Butz N, Banfi A et al (2008) B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart. Cardiovasc Res 80(1):106–113

    Article  CAS  PubMed  Google Scholar 

  51. Schremmer-Danninger E, Heinz-Erian P, Topfer-Petersen E, Rosher AA (1995) Autoradiographic localization and characterization of bradykinin receptors in human skin. Eur J Pharmacol 283(1–3):207–216

    Article  CAS  PubMed  Google Scholar 

  52. Schremmer-Danninger E, Hermann A, Fink E, Fritz H, Roscher AA (1999) Identification and occurrence of mRNAs for components of the kallikrein-kinin system in human skin and in skin diseases. Immunopharmacology 43(2–3):287–291

    Article  CAS  PubMed  Google Scholar 

  53. Schremmer-Danninger E, Naidoo S, Neuhof C, Valeske K, Snyman C, Sander C et al (2004) Visualisation of tissue kallikrein, kininogen and kinin receptors in human skin following trauma and in dermal diseases. Biol Chem 385(11):1069–1076

    Article  CAS  PubMed  Google Scholar 

  54. Shiraki Y, Ishibashi Y, Hiruma M, Nishikawa A, Ikeda S (2006) Cytokine secretion profiles of human keratinocytes during Trichophyton tonsurans and Arthroderma benhamiae infections. J Med Microbiol 55(Pt 9):1175–1185

    Article  CAS  PubMed  Google Scholar 

  55. Taub JS, Guo R, Leeb-Lundberg LM, Madden JF, Daaka Y (2003) Bradykinin receptor subtype 1 expression and function in prostate cancer. Cancer Res 63(9):2037–2041

    CAS  PubMed  Google Scholar 

  56. Toi M, Harris AL, Bicknell R (1991) Interleukin-4 is a potent mitogen for capillary endothelium. Biochem Biophys Res Commun 174(3):1287–1293

    Article  CAS  PubMed  Google Scholar 

  57. Trompezinski S, Denis A, Vinche A, Schmitt D, Viac J (2002) IL-4 and interferon-gamma differentially modulate vascular endothelial growth factor release from normal human keratinocytes and fibroblasts. Exp Dermatol 11(3):224–231

    Article  CAS  PubMed  Google Scholar 

  58. Vidal MA, Astroza A, Matus CE et al (2005) Kinin B2 receptor-coupled signal transduction in human cultured keratinocytes. J Invest Dermatol 124(1):178–186

    Article  CAS  PubMed  Google Scholar 

  59. Watson A, Morris VL, Chan BM (2009) Coordinated integrin and growth factor regulation of primary keratinocyte migration mediated through extracellular signal regulated kinase and phosphoinositide 3-kinase. Arch Dermatol Res 301(4):307–317

    Article  CAS  PubMed  Google Scholar 

  60. Xu Y, Zhang Y, Cardell LO (2010) Nicotine enhances murine airway contractile responses to kinin receptor agonists via activation of JNK- and PDE4-related intracellular pathways. Respir Res 11:13

    Article  PubMed Central  PubMed  Google Scholar 

  61. Yu XJ, Ren XH, Xu YH, Chen LM, Zhou CL, Li CY (2010) Vasoactive intestinal peptide induces vascular endothelial growth factor production in human HaCaT keratinocytes via MAPK pathway. Neuropeptides 44(5):407–411

    Article  CAS  PubMed  Google Scholar 

  62. Zenz R, Wagner EF (2006) Jun signalling in the epidermis: from developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol 38(7):1043–1049

    Article  CAS  PubMed  Google Scholar 

  63. Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D et al (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437(7057):369–375

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants 3130385 (CM) and 1110464 (CDF) from Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT, Chile), a Ph.D. Fellowship 63080006 (AJM) from Consejo Nacional de Ciencia y Tecnologia (CONICYT, Chile), and Grant D-2010-02 (AJM) from Direccion de Investigacion y Desarrollo, Universidad Austral de Chile (Chile). The authors also wish to thank Dr. Jose Sarmiento for his help and technical support with measurements of [Ca2+]i and Prof. Kanti D. Bhoola for the critical reading of the manuscript and helpful suggestions.

Author information

Authors and Affiliations

  1. Laboratorio de Patologia Celular, Instituto de Anatomia, Histologia y Patologia, Universidad Austral de Chile, Isla Teja, PO Box 567, Valdivia, Chile

    Astrid J. Mejia, Carola E. Matus, Francisca Pavicic, Miguel Concha, Pamela Ehrenfeld & Carlos D. Figueroa

Authors
  1. Astrid J. Mejia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carola E. Matus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisca Pavicic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miguel Concha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pamela Ehrenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos D. Figueroa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos D. Figueroa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mejia, A.J., Matus, C.E., Pavicic, F. et al. Intracellular signaling pathways involved in the release of IL-4 and VEGF from human keratinocytes by activation of kinin B1 receptor: functional relevance to angiogenesis. Arch Dermatol Res 307, 803–817 (2015). https://doi.org/10.1007/s00403-015-1595-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-015-1595-6

Keywords

Search

Navigation