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. 1998 Apr 1;101(7):1509–1518. doi: 10.1172/JCI171

Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis.

Z Bata-Csorgo 1, K D Cooper 1, K M Ting 1, J J Voorhees 1, C Hammerberg 1
PMCID: PMC508729  PMID: 9525994

Abstract

In addition to being T lymphocyte-driven, psoriasis may be due in part to abnormal integrin expression. Normal-appearing (uninvolved) skin from psoriatic patients was examined to determine whether altered fibronectin or its receptor expression is detectable before development of psoriatic lesions. In contrast to skin from normal subjects, we detect by immunofluorescence the abnormal presence of plasma fibronectin in the basal cell layer of the epidermis of psoriatic uninvolved skin. Furthermore, increased fibronectin exposure superinduces the in vitro cell cycle induction and expansion of psoriatic nonlesional keratinocytes in response to a cocktail of T cell lymphokines. Fibronectin alone also appeared to increase cell cycle entry among uninvolved but not normal keratinocytes. Concordantly, the alpha5 integrin fibronectin receptor, but not alpha2 or alpha3, is overexpressed in the in vivo nonlesional psoriatic epidermis. The involvement of alpha5beta1 in the early outgrowth of clonogenic keratinocytes in the ex vivo culture was demonstrated by the ability of anti-alpha5 mAb to inhibit keratinocyte growth on fibronectin. Thus, the fibronectin receptor appears to be one of the components required for the development of the hyperresponsiveness of psoriatic keratinocytes to signals for proliferation provided by lymphokines produced by intralesional T lymphocytes in psoriasis.

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Selected References

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  1. Adams J. C., Watt F. M. Regulation of development and differentiation by the extracellular matrix. Development. 1993 Apr;117(4):1183–1198. doi: 10.1242/dev.117.4.1183. [DOI] [PubMed] [Google Scholar]
  2. Baadsgaard O., Tong P., Elder J. T., Hansen E. R., Ho V., Hammerberg C., Lange-Vejlsgaard G., Fox D. A., Fisher G., Chan L. S. UM4D4+ (CDw60) T cells are compartmentalized into psoriatic skin and release lymphokines that induce a keratinocyte phenotype expressed in psoriatic lesions. J Invest Dermatol. 1990 Sep;95(3):275–282. doi: 10.1111/1523-1747.ep12484908. [DOI] [PubMed] [Google Scholar]
  3. Bata-Csorgo Z., Hammerberg C., Voorhees J. J., Cooper K. D. Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis. J Exp Med. 1993 Oct 1;178(4):1271–1281. doi: 10.1084/jem.178.4.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bata-Csorgo Z., Hammerberg C., Voorhees J. J., Cooper K. D. Intralesional T-lymphocyte activation as a mediator of psoriatic epidermal hyperplasia. J Invest Dermatol. 1995 Jul;105(1 Suppl):89S–94S. doi: 10.1111/1523-1747.ep12316121. [DOI] [PubMed] [Google Scholar]
  5. Bata-Csorgo Z., Hammerberg C., Voorhees J. J., Cooper K. D. Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J Clin Invest. 1995 Jan;95(1):317–327. doi: 10.1172/JCI117659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bernard B. A., Robinson S. M., Vandaele S., Mansbridge J. N., Darmon M. Abnormal maturation pathway of keratinocytes in psoriatic skin. Br J Dermatol. 1985 Jun;112(6):647–653. doi: 10.1111/j.1365-2133.1985.tb02332.x. [DOI] [PubMed] [Google Scholar]
  7. Carroll J. M., Romero M. R., Watt F. M. Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis. Cell. 1995 Dec 15;83(6):957–968. doi: 10.1016/0092-8674(95)90211-2. [DOI] [PubMed] [Google Scholar]
  8. Chen Q., Kinch M. S., Lin T. H., Burridge K., Juliano R. L. Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem. 1994 Oct 28;269(43):26602–26605. [PubMed] [Google Scholar]
  9. Delcommenne M., Streuli C. H. Control of integrin expression by extracellular matrix. J Biol Chem. 1995 Nov 10;270(45):26794–26801. doi: 10.1074/jbc.270.45.26794. [DOI] [PubMed] [Google Scholar]
  10. Fyrand O. Studies on fibronectin in the skin. II. Indirect immunofluorescence studies in psoriasis vulgaris. Arch Dermatol Res. 1979 Aug;266(1):33–41. doi: 10.1007/BF00412860. [DOI] [PubMed] [Google Scholar]
  11. Giannelli G., Savoia P., Schiraldi O., Lospalluti M., De Luca M., Marchisio P. C., Quaranta V. Psoriatic lesions in patients with chronic liver disease are distinct from psoriasis vulgaris lesions, as judged on basis of integrin adhesion receptors. Hepatology. 1994 Jul;20(1 Pt 1):56–65. doi: 10.1016/0270-9139(94)90134-1. [DOI] [PubMed] [Google Scholar]
  12. Gospodarowicz D., Greenburg G., Birdwell C. R. Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res. 1978 Nov;38(11 Pt 2):4155–4171. [PubMed] [Google Scholar]
  13. Gottlieb S. L., Gilleaudeau P., Johnson R., Estes L., Woodworth T. G., Gottlieb A. B., Krueger J. G. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med. 1995 May;1(5):442–447. doi: 10.1038/nm0595-442. [DOI] [PubMed] [Google Scholar]
  14. Hansen L. K., Mooney D. J., Vacanti J. P., Ingber D. E. Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth. Mol Biol Cell. 1994 Sep;5(9):967–975. doi: 10.1091/mbc.5.9.967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heng M. C., Allen S. G., Haberfelde G., Song M. K. Electron microscopic and immunocytochemical studies of the sequence of events in psoriatic plaque formation following tape-stripping. Br J Dermatol. 1991 Dec;125(6):548–556. doi: 10.1111/j.1365-2133.1991.tb14792.x. [DOI] [PubMed] [Google Scholar]
  16. Heng M. C., Kloss S. G., Kuehn C. S., Chase D. G. Significance and pathogenesis of basal keratinocyte herniations in psoriasis. J Invest Dermatol. 1986 Sep;87(3):362–366. doi: 10.1111/1523-1747.ep12524814. [DOI] [PubMed] [Google Scholar]
  17. Huang S., Varani J., Chakrabarty S. Control of AKR fibroblast phenotype by fibronectin: regulation of cell-surface fibronectin binding receptor by fibronectin. J Cell Physiol. 1994 Dec;161(3):470–482. doi: 10.1002/jcp.1041610310. [DOI] [PubMed] [Google Scholar]
  18. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  19. Ingber D. E. Fibronectin controls capillary endothelial cell growth by modulating cell shape. Proc Natl Acad Sci U S A. 1990 May;87(9):3579–3583. doi: 10.1073/pnas.87.9.3579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jaskulski D., deRiel J. K., Mercer W. E., Calabretta B., Baserga R. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science. 1988 Jun 10;240(4858):1544–1546. doi: 10.1126/science.2897717. [DOI] [PubMed] [Google Scholar]
  21. Javier A. F., Bata-Csorgo Z., Ellis C. N., Kang S., Voorhees J. J., Cooper K. D. Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J Clin Invest. 1997 May 1;99(9):2094–2099. doi: 10.1172/JCI119382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Juhasz I., Murphy G. F., Yan H. C., Herlyn M., Albelda S. M. Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol. 1993 Nov;143(5):1458–1469. [PMC free article] [PubMed] [Google Scholar]
  23. Kim J. P., Zhang K., Chen J. D., Wynn K. C., Kramer R. H., Woodley D. T. Mechanism of human keratinocyte migration on fibronectin: unique roles of RGD site and integrins. J Cell Physiol. 1992 Jun;151(3):443–450. doi: 10.1002/jcp.1041510303. [DOI] [PubMed] [Google Scholar]
  24. Klein C. E., Steinmayer T., Mattes J. M., Kaufmann R., Weber L. Integrins of normal human epidermis: differential expression, synthesis and molecular structure. Br J Dermatol. 1990 Aug;123(2):171–178. doi: 10.1111/j.1365-2133.1990.tb01844.x. [DOI] [PubMed] [Google Scholar]
  25. Kubo M., Norris D. A., Howell S. E., Ryan S. R., Clark R. A. Human keratinocytes synthesize, secrete, and deposit fibronectin in the pericellular matrix. J Invest Dermatol. 1984 Jun;82(6):580–586. doi: 10.1111/1523-1747.ep12261325. [DOI] [PubMed] [Google Scholar]
  26. LaFlamme S. E., Akiyama S. K., Yamada K. M. Regulation of fibronectin receptor distribution. J Cell Biol. 1992 Apr;117(2):437–447. doi: 10.1083/jcb.117.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lortat-Jacob H., Grimaud J. A. Binding of interferon-gamma to heparan sulfate is restricted to the heparin-like domains and involves carboxylic--but not N-sulfated--groups. Biochim Biophys Acta. 1992 Sep 15;1117(2):126–130. doi: 10.1016/0304-4165(92)90069-7. [DOI] [PubMed] [Google Scholar]
  28. Lortat-Jacob H., Grimaud J. A. Interferon-gamma C-terminal function: new working hypothesis. Heparan sulfate and heparin, new targets for IFN-gamma, protect, relax the cytokine and regulate its activity. Cell Mol Biol. 1991;37(3):253–260. [PubMed] [Google Scholar]
  29. Lortat-Jacob H., Kleinman H. K., Grimaud J. A. High-affinity binding of interferon-gamma to a basement membrane complex (matrigel). J Clin Invest. 1991 Mar;87(3):878–883. doi: 10.1172/JCI115093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Miyamoto S., Akiyama S. K., Yamada K. M. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science. 1995 Feb 10;267(5199):883–885. doi: 10.1126/science.7846531. [DOI] [PubMed] [Google Scholar]
  31. Mondello M. R., Magaudda L., Pergolizzi S., Santoro A., Vaccaro M., Califano L., Cannavò S. P., Guarneri B. Behaviour of laminin 1 and type IV collagen in uninvolved psoriatic skin. Immunohistochemical study using confocal laser scanning microscopy. Arch Dermatol Res. 1996 Aug;288(9):527–531. doi: 10.1007/BF02505249. [DOI] [PubMed] [Google Scholar]
  32. O'Keefe E. J., Woodley D., Castillo G., Russell N., Payne R. E., Jr Production of soluble and cell-associated fibronectin by cultured keratinocytes. J Invest Dermatol. 1984 Feb;82(2):150–155. doi: 10.1111/1523-1747.ep12259708. [DOI] [PubMed] [Google Scholar]
  33. Pellegrini G., De Luca M., Orecchia G., Balzac F., Cremona O., Savoia P., Cancedda R., Marchisio P. C. Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin. J Clin Invest. 1992 Jun;89(6):1783–1795. doi: 10.1172/JCI115782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pinkus H., Mehregan A. H. The primary histologic lesion of seborrheic dermatitis and psoriasis. J Invest Dermatol. 1966 Jan;46(1):109–116. doi: 10.1038/jid.1966.16. [DOI] [PubMed] [Google Scholar]
  35. Roberts R., Gallagher J., Spooncer E., Allen T. D., Bloomfield F., Dexter T. M. Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature. 1988 Mar 24;332(6162):376–378. doi: 10.1038/332376a0. [DOI] [PubMed] [Google Scholar]
  36. Schwartz M. A., Ingber D. E. Integrating with integrins. Mol Biol Cell. 1994 Apr;5(4):389–393. doi: 10.1091/mbc.5.4.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schwartz M. A., Lechene C., Ingber D. E. Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin alpha 5 beta 1, independent of cell shape. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7849–7853. doi: 10.1073/pnas.88.17.7849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schwartz M. A. Signaling by integrins: implications for tumorigenesis. Cancer Res. 1993 Apr 1;53(7):1503–1506. [PubMed] [Google Scholar]
  39. Strange P., Cooper K. D., Hansen E. R., Fisher G., Larsen J. K., Fox D., Krag C., Voorhees J. J., Baadsgaard O. T-lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation. J Invest Dermatol. 1993 Nov;101(5):695–700. doi: 10.1111/1523-1747.ep12371678. [DOI] [PubMed] [Google Scholar]
  40. Symington B. E. Fibronectin receptor modulates cyclin-dependent kinase activity. J Biol Chem. 1992 Dec 25;267(36):25744–25747. [PubMed] [Google Scholar]
  41. Symington B. E. Growth signalling through the alpha 5 beta 1 fibronectin receptor. Biochem Biophys Res Commun. 1995 Mar 8;208(1):126–134. doi: 10.1006/bbrc.1995.1314. [DOI] [PubMed] [Google Scholar]
  42. Takashima A., Billingham R. E., Grinnell F. Activation of rabbit keratinocyte fibronectin receptor function in vivo during wound healing. J Invest Dermatol. 1986 May;86(5):585–590. doi: 10.1111/1523-1747.ep12355243. [DOI] [PubMed] [Google Scholar]
  43. Takashima A., Grinnell F. Fibronectin-mediated keratinocyte migration and initiation of fibronectin receptor function in vitro. J Invest Dermatol. 1985 Oct;85(4):304–308. doi: 10.1111/1523-1747.ep12276880. [DOI] [PubMed] [Google Scholar]
  44. Toda K., Tuan T. L., Brown P. J., Grinnell F. Fibronectin receptors of human keratinocytes and their expression during cell culture. J Cell Biol. 1987 Dec;105(6 Pt 2):3097–3104. doi: 10.1083/jcb.105.6.3097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tran Van Nhieu G., Isberg R. R. Bacterial internalization mediated by beta 1 chain integrins is determined by ligand affinity and receptor density. EMBO J. 1993 May;12(5):1887–1895. doi: 10.1002/j.1460-2075.1993.tb05837.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Varner J. A., Emerson D. A., Juliano R. L. Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol Biol Cell. 1995 Jun;6(6):725–740. doi: 10.1091/mbc.6.6.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Verschoore M., Kowalewski C., Chorzelska M. J., Bernard B. A., Darmon Y. M. Intraepidermal leakage of plasma proteins after tape stripping of normal skin and uninvolved psoriatic skin. Br J Dermatol. 1990 Mar;122(3):391–397. doi: 10.1111/j.1365-2133.1990.tb08288.x. [DOI] [PubMed] [Google Scholar]
  48. Xu J., Clark R. A. Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol. 1996 Jan;132(1-2):239–249. doi: 10.1083/jcb.132.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Xu S., Ariizumi K., Edelbaum D., Bergstresser P. R., Takashima A. Cytokine-dependent regulation of growth and maturation in murine epidermal dendritic cell lines. Eur J Immunol. 1995 Apr;25(4):1018–1024. doi: 10.1002/eji.1830250424. [DOI] [PubMed] [Google Scholar]
  50. Zambruno G., Marchisio P. C., Marconi A., Vaschieri C., Melchiori A., Giannetti A., De Luca M. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J Cell Biol. 1995 May;129(3):853–865. doi: 10.1083/jcb.129.3.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zhu X., Assoian R. K. Integrin-dependent activation of MAP kinase: a link to shape-dependent cell proliferation. Mol Biol Cell. 1995 Mar;6(3):273–282. doi: 10.1091/mbc.6.3.273. [DOI] [PMC free article] [PubMed] [Google Scholar]

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