T Cell Integrin Activation by Chemokines in Inflammation

  • Yoshiya Tanaka


The adhesive function of integrins is regulated through cytoplasmic signaling induced by several stimuli, whose process is designated as “inside-out signaling”. A large number of lymphocytes are recruited to the sites of inflammation where they form an essential component of the response to infection, injury, autoimmune disorders, allergy, tumor invasion, atherosclerosis and so on. The recruitment of leukocytes into tissue is regulated by a sequences of interactions between the circulating leukocytes and the endothelial cells. Leukocyte integrins play a pivotal role in leukocyte adhesion to endothelial cells. During the process, the activation of integrins by chemokines is essential for integrin-mediated adhesion in which a signal transduced to the leukocyte converts the functionally inactive integrin to an active adhesive configuration. The present review documents the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines during inflammatory processes.

Key words

T lymphocytes recirculation/recruitment adhesion molecules integrins chemokines inflammation. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams D. H., Harvath L., Bottaro D. P., Interrante R., Catalano G., Tanaka Y., Strain A., Hubscher S. G. and Shaw S. (1994): Hepatocyte growth factor and macrophage inflammatory protein-1[3: structurally distinct cytokines that induce rapid cytoskeletal changes and subset--preferential migration in T cells. Proc. Natl. Acad. Sci. USA, 91, 7144–7148.PubMedCrossRefGoogle Scholar
  2. Adams D. H., Yannelli J. R., Newman W., Lawley T., Ades E., Rosenberg S. A. and Shaw S. (1997): Adhesion of tumour-infiltrating lymphocytes to endothelium: a phenotypic and functional analysis. Br. J. Cancer, 75, 1421–1431.PubMedCrossRefGoogle Scholar
  3. Bemfield M., Kokenyesi R., Kato M., Hinkes M. T., Spring J., Gallo R. L. and Lose E. J. (1992): Biology of the syndecans: a family of transmembrane heparan sulphate proteoglycans. Annu. Rev. Cell Biol., 8, 365–393.CrossRefGoogle Scholar
  4. Bokoch G. M. (1995): Chemoattractant signaling and leukocyte activation. Blood, 86, 1649–1655.PubMedGoogle Scholar
  5. Bubb M. R., Baines I. C. and Korn E. D. (1998): Localization of actobindin, profilin I, profil-in II, and phosphatidylinositol-4,5-bisphosphate (PIP2) in Acanthamoeba castellanii. Cell Motil. Cytoskeleton, 39, 134–146.CrossRefGoogle Scholar
  6. Butcher E. C. (1991): Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell, 67, 1033–1036.PubMedCrossRefGoogle Scholar
  7. Camphell J. J., Qin S., Bacon K. B., Mackay C. R. and Butcher E. C. (1996): Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion--triggering versus chemotactic responses in lymphoid cells. J. Cell Biol., 255, 134–141.Google Scholar
  8. Carlier M. F. and Pantaloni D. (1997): Control of actin dynamics in cell motility. J. Mol. Biol., 269, 459–467.PubMedCrossRefGoogle Scholar
  9. Chan A. S., Mobley J. L., Fields G. B. and Shimizu Y. (1997): CD7-mediated regulation of integrin adhesiveness on human T cells involves tyrosine phosphorylation-dependent activation of phosphatidylinositol 3-kinase. J. Immunol., 159, 934–942.PubMedGoogle Scholar
  10. Chaudhary A., Chen J., Gu Q. M., Witke W., Kwiatkowski D. J. and Prestwich G. D. (1998): Probing the phosphoinositide 4,5-bisphosphate binding site of human profilin I. Chem. Biol., 5. 273–281.PubMedCrossRefGoogle Scholar
  11. Pozo M. A., Sanchez-Meteos P., Nieto M. and Sanchez-Madrid F. (1996): Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix: involvement of cAMP signaling pathway. J. Cell Biol., 131, 495–508.CrossRefGoogle Scholar
  12. Hughes P. E., Renshaw M. W., Pfaff M., Forsyth J., Keivens V. M., Schwartz M. A. and Ginsberg M. H. (1997): Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell, 88, 521–530.PubMedCrossRefGoogle Scholar
  13. Jackson D. G., Bell J. I., Dickinson R., Timans J., Shields J. and Whittle N. (1995): Proteoglycan forms of the lymphocyte homing receptor CD44 are alternatively splice variants containing the v3 exon. J. Cell Biol., 128, 673–682.PubMedCrossRefGoogle Scholar
  14. Korenbaum E., Nordberg P., Bjorkegren Sjogren C., Schutt C. E., Lindberg U. and Karisson R. (1998): The role of profilin in actin polymerization and nucleotide exchange. Biochemistry, 37, 9274–9283.PubMedCrossRefGoogle Scholar
  15. Laudanna C., Campbell J. J. and Butcher E. C. (1996): Role of Rho in chemoattractant-activated leukocyte adhesion through integrins. Science, 271, 981–983.PubMedCrossRefGoogle Scholar
  16. Liao F., Rabin R. L., Yannelli J. R., Koniaris L. G., Vanguri P. and Farber J. M. (1995): Human Mig chemokine: biochemical and functional characterization. J. Exp. Med., 182, 1301–1314.PubMedCrossRefGoogle Scholar
  17. Luque A., Gomez M., Puzon W., Takada Y., Sanchez-Madrid E. and Cabanas C. (1996): Activated conformation of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355–425) of the common (31 chain. J. Biol. Chem., 271, 11067–11075.PubMedCrossRefGoogle Scholar
  18. Mackay C. R. (1996): Chemokine receptors and T cell chemotaxis. J. Exp. Med., 184, 799–802.PubMedCrossRefGoogle Scholar
  19. Marshall C. J. (1996): Ras effectors. Curr. Opin. Cell. Biol., 8, 197–204.PubMedCrossRefGoogle Scholar
  20. Mertens G., Schueren B. van der, Berghe H. van den and David G. (1996): Heparan sulfate expression in polarized epithelial cells: The apical sorting of glypican (GPI-anchored proteoglycan) is inversely related to its heparan sulfate content. J. Cell Biol., 132, 487–495.PubMedCrossRefGoogle Scholar
  21. Metzner B., Heger M., Hofmann C., Czech W. and Norgauer J. (1997): Evidence for the involvement of phosphatidylinositol 4,5-bisphosphate 3-kinase in CD18-mediated adhesion of human neutrophils to fibrinogen. Biochem. Biophys. Res. Commun., 232, 719–723.PubMedCrossRefGoogle Scholar
  22. Newton R. A., Thiel M. and Hogg N. (1997): Signaling mechanisms and the activation of leukocyte integrins. J. Leukoc. Biol., 61, 422–426.PubMedGoogle Scholar
  23. Proost P., Wuyts A. and van Damme J. (1996): The role of chemokines in inflammation. Int. J. Clin. Lab. Res., 26, 211–223.PubMedCrossRefGoogle Scholar
  24. Schluter K., Jockusch B. M. and Rothkegel M. (1997): Profilins as regulators of actin dynamics. Biochem. Biophys. Acta, 1359, 97–109.Google Scholar
  25. Shimizu Y. (1996): Intracellular signaling pathways and the regulation of cell adhesion. Hum. Cell, 9, 175–180.PubMedGoogle Scholar
  26. Shimizu Y. and Hunt III S. W. (1996): Regulating integrin-mediated adhesion: one more function for PI 3-kinase? Immunol. Today, 17, 565–573.Google Scholar
  27. Shimizu Y., Newman W., Tanaka Y. and Shaw S. (1992): Lymphocyte interactions with endothelial cells. Immunol. Today, 13, 106–112.PubMedCrossRefGoogle Scholar
  28. Terkeitaub R., Boisvert W. A. and Curtiss L. K. (1998): Chemokines and atherosclerosis. Curr. Opin. Lipidol., 9, 397–405.CrossRefGoogle Scholar
  29. Sohn R. H., Chen J., Koblan K. S., Bray P. F. and Goldschmidt-Clermont P. J. (1995): Localization of a binding site for phosphatidylinositol 4,5-bisphosphate on human profilin. J. Biol. Chem., 270, 21114–21120.PubMedCrossRefGoogle Scholar
  30. Sohn R. H. and Goldschmidt-Clermont R J. (1994): Profilin: at the crossroads of signal transduction and the actin cytoskeleton. Bioessays, 16, 465–478.PubMedCrossRefGoogle Scholar
  31. Springer T. A. (1995): Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol., 57, 827–872.PubMedCrossRefGoogle Scholar
  32. Stewart M. P., Cabanas C. and Hogg N. (1996): T cell adhesion to intercellular adhesion molecule-1 (ICAM-1) is controlled by cell spreading and the activation of integrin LFA-1. J. Immunol., 156, 1810–1819.PubMedGoogle Scholar
  33. Tanaka Y., Adams D. H., Hubscher S., Hirano H., Siebenlist U. and Shaw S. (1993a): T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-113. Nature, 361, 79–82.PubMedCrossRefGoogle Scholar
  34. Tanaka Y., Adams D. H. and Shaw S. (1993b): Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes. Immunol. Today, 14, 111–115.PubMedCrossRefGoogle Scholar
  35. Tanaka Y., Albelda S. M., Horgan K. J., van Seventer G. A., Shimizu Y., Newman W., Hallam J., Newman P. J., Buck C. A. and Shaw S. (1992): CD31 expressed on distinctive T cell sub- sets is a preferential amplifier of 131 integrin-mediated adhesion. J. Exp. Med., 176, 245–253.PubMedCrossRefGoogle Scholar
  36. Tanaka Y. and Aso M. (1998): Chemokine and cellular adhesion in the context of heparan sulfate proteoglycan. Trends. Glycosci. Glycotech., 10, 153–160.CrossRefGoogle Scholar
  37. Tanaka Y., Fujii K., Hubscher S., Aso M., Takazawa A., Saito K., Ota T. and Eto S. (1998a): Heparan sulfate proteoglycan on endothelium efficiently induces integrin-mediated T cell adhesion by immobilizing chemokines in rheumatoid synovitis. Arthritis Rheum., 41, 1365–1377.PubMedCrossRefGoogle Scholar
  38. Tanaka Y., Kimata K., Adams D. H. and Eto S. (1998b): Modulation of cytokine function by heparan sulfate proteoglycans: sophisticated models for the regulation of cellular responses to cytokines. Proc. Assoc. Am. Physicians, 110, 118–125.PubMedGoogle Scholar
  39. Tanaka Y., Kimata K., Wake A., Mine S., Morimoto I., Yamakawa N., Habuchi H., Ashikari S., Yamamoto H., Sakurai K., Yoshida K., Suzuki S. and Eto S. (1996): Heparan sulfate proteoglycan on leukemic cells is primarily involved in integrin triggering and its mediated adhesion to endothelial cells. J. Exp. Med., 184, 1987–1997.PubMedCrossRefGoogle Scholar
  40. Tanaka Y., Minami Y., Mine S., Hirano H., Hu C.-D., Fujimoto H., Fujii K., Saito K., Tsukada J., van Kooyk Y, Figdor C. G., Kataoka T. and Eto S. (1999): H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells. J. Immunol., 163, 6209–6216.PubMedGoogle Scholar
  41. Tanaka Y., Mine S., Figdor C. G., Wake A., Hirano H., Tsukada J., Aso M., Fujii K., Saito K., van Kooyk Y. and Eto S. (1998c): Constitutive chemokine production results in activation of LFA-1 on adult T cell leukemia cells. Blood, 91, 3909–3919.PubMedGoogle Scholar
  42. Tanaka Y., Mine S., Hanagiri T., Hiraga T., Morimoto I., Figdor C. G., van Kooyk Y., Ozawa H., Nakamura T., Yasumoto K. and Eto S. (1998d): Constitutive up-regulation of integrin-mediated adhesion of tumor-infiltrating lymphocytes to osteoblasts and bone marrow-derived stromal cells. Cancer Res., 58, 4138–4145.PubMedGoogle Scholar
  43. Kooyk Y., Weder P., Heije K. and Figdor C. G. (1994): Extracellular Cat+ modulates leukocyte function-associated antigen-1 cell surface distribution on T lymphocytes and consequently affects cell adhesion. J. Cell Biol., 124, 1061–1070.PubMedCrossRefGoogle Scholar
  44. Webb L. M. C., Ehrengruber M. U., Ian C. and Marco B. (1993): Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc. Natl. Acad. Sci. USA, 90, 7158–7162.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • Yoshiya Tanaka
    • 1
  1. 1.The First Department of Internal MedicineUniversity of Occupational and Environmental Health, School of MedicineKitakyushuJapan

Personalised recommendations