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. 1995 Jan;95(1):264–271. doi: 10.1172/JCI117650

Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells.

M F Iademarco 1, J L Barks 1, D C Dean 1
PMCID: PMC295423  PMID: 7529260

Abstract

Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and alpha 4 integrins on leukocytes is thought to mediate the selective recruitment of eosinophils and lymphocytes that occurs in allergic diseases. IL-4 is associated with allergic conditions, and it has been shown to selectively increase expression of VCAM-1 on endothelial cells in vivo, suggesting that it could be responsible for VCAM-1 expression in allergic disease. Using a combination of immunofluorescence, flow cytometry, and Northern analysis, we compared the effect of TNF-alpha and IL-4 on VCAM-1 expression. TNF-alpha is also associated with allergic diseases, and it rapidly increases transcription of the VCAM-1 gene. The effect of IL-4 was relatively modest with prolonged kinetics: VCAM-1 was not detected until 72 h after treatment with IL-4. However, when TNF-alpha and IL-4 were combined, there was a synergistic increase in VCAM-1 expression and a dramatic prolongation of the appearance of VCAM-1 on the cell surface. This synergy results from a combination of transcriptional activation by TNF-alpha and the stabilization of resulting transcripts by IL-4. We propose that IL-4 allows subthreshold concentrations of TNF-alpha (concentrations that would not normally activate expression of adhesion molecules on the endothelium) to selectively increase VCAM-1 expression and to prolong its appearance on the surface of cells in allergic disease.

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Selected References

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  1. Akahane K., Pluznik D. H. Interleukin-4 inhibits interleukin-1 alpha-induced granulocyte-macrophage colony-stimulating factor gene expression in a murine B-lymphocyte cell line via downregulation of RNA precursor. Blood. 1992 Jun 15;79(12):3188–3195. [PubMed] [Google Scholar]
  2. Arm J. P., Lee T. H. The pathobiology of bronchial asthma. Adv Immunol. 1992;51:323–382. doi: 10.1016/s0065-2776(08)60491-5. [DOI] [PubMed] [Google Scholar]
  3. Bacchi C. E., Marsh C. L., Perkins J. D., Carithers R. L., Jr, McVicar J. P., Hudkins K. L., Benjamin C. D., Harlan J. M., Lobb R., Alpers C. E. Expression of vascular cell adhesion molecule (VCAM-1) in liver and pancreas allograft rejection. Am J Pathol. 1993 Feb;142(2):579–591. [PMC free article] [PubMed] [Google Scholar]
  4. Baltimore D. The Gerhard Domagk Lecture. Transcription factors in lymphoid development. Ann N Y Acad Sci. 1993 Jun 23;685:420–428. doi: 10.1111/j.1749-6632.1993.tb35901.x. [DOI] [PubMed] [Google Scholar]
  5. Beekhuizen H., Verdegaal E. M., Blokland I., van Furth R. Contribution of ICAM-1 and VCAM-1 to the morphological changes in monocytes bound to human venous endothelial cells stimulated with recombinant interleukin-4 (rIL-4) or rIL-1 alpha. Immunology. 1992 Nov;77(3):469–472. [PMC free article] [PubMed] [Google Scholar]
  6. Bentley A. M., Durham S. R., Robinson D. S., Menz G., Storz C., Cromwell O., Kay A. B., Wardlaw A. J. Expression of endothelial and leukocyte adhesion molecules interacellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 in the bronchial mucosa in steady-state and allergen-induced asthma. J Allergy Clin Immunol. 1993 Dec;92(6):857–868. doi: 10.1016/0091-6749(93)90064-m. [DOI] [PubMed] [Google Scholar]
  7. Bevilacqua M. P. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. doi: 10.1146/annurev.iy.11.040193.004003. [DOI] [PubMed] [Google Scholar]
  8. Bevilacqua M. P., Pober J. S., Mendrick D. L., Cotran R. S., Gimbrone M. A., Jr Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9238–9242. doi: 10.1073/pnas.84.24.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bradding P., Feather I. H., Wilson S., Bardin P. G., Heusser C. H., Holgate S. T., Howarth P. H. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol. 1993 Oct 1;151(7):3853–3865. [PubMed] [Google Scholar]
  10. Briscoe D. M., Cotran R. S., Pober J. S. Effects of tumor necrosis factor, lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule-1 in vivo. Correlation with CD3+ T cell infiltration. J Immunol. 1992 Nov 1;149(9):2954–2960. [PubMed] [Google Scholar]
  11. Briscoe D. M., Schoen F. J., Rice G. E., Bevilacqua M. P., Ganz P., Pober J. S. Induced expression of endothelial-leukocyte adhesion molecules in human cardiac allografts. Transplantation. 1991 Feb;51(2):537–539. [PubMed] [Google Scholar]
  12. Brusselle G. G., Kips J. C., Tavernier J. H., van der Heyden J. G., Cuvelier C. A., Pauwels R. A., Bluethmann H. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy. 1994 Jan;24(1):73–80. doi: 10.1111/j.1365-2222.1994.tb00920.x. [DOI] [PubMed] [Google Scholar]
  13. Chin Y. H., Cai J. P., Xu X. M. Tissue-specific homing receptor mediates lymphocyte adhesion to cytokine-stimulated lymph node high endothelial venule cells. Immunology. 1991 Nov;74(3):478–483. [PMC free article] [PubMed] [Google Scholar]
  14. Collins T., Williams A., Johnston G. I., Kim J., Eddy R., Shows T., Gimbrone M. A., Jr, Bevilacqua M. P. Structure and chromosomal location of the gene for endothelial-leukocyte adhesion molecule 1. J Biol Chem. 1991 Feb 5;266(4):2466–2473. [PubMed] [Google Scholar]
  15. Dean D. C., Newby R. F., Bourgeois S. Regulation of fibronectin biosynthesis by dexamethasone, transforming growth factor beta, and cAMP in human cell lines. J Cell Biol. 1988 Jun;106(6):2159–2170. doi: 10.1083/jcb.106.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Degitz K., Li L. J., Caughman S. W. Cloning and characterization of the 5'-transcriptional regulatory region of the human intercellular adhesion molecule 1 gene. J Biol Chem. 1991 Jul 25;266(21):14024–14030. [PubMed] [Google Scholar]
  17. Donnelly R. P., Fenton M. J., Kaufman J. D., Gerrard T. L. IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol. 1991 May 15;146(10):3431–3436. [PubMed] [Google Scholar]
  18. Durham S. R., Ying S., Varney V. A., Jacobson M. R., Sudderick R. M., Mackay I. S., Kay A. B., Hamid Q. A. Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia. J Immunol. 1992 Apr 15;148(8):2390–2394. [PubMed] [Google Scholar]
  19. Elices M. J., Osborn L., Takada Y., Crouse C., Luhowskyj S., Hemler M. E., Lobb R. R. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990 Feb 23;60(4):577–584. doi: 10.1016/0092-8674(90)90661-w. [DOI] [PubMed] [Google Scholar]
  20. Finn P. W., Kara C. J., Grusby M. J., Folsom V., Glimcher L. H. Upstream elements of the MHC class II E beta gene active in B cells. J Immunol. 1991 Jun 1;146(11):4011–4015. [PubMed] [Google Scholar]
  21. Galea P., Chartier A., Lebranchu Y. Increased lymphocyte adhesion to allogeneic endothelial cells by interleukin-4 (IL-4). Transplant Proc. 1991 Feb;23(1 Pt 1):243–244. [PubMed] [Google Scholar]
  22. Galéa P., Lebranchu Y., Thibault G., Bardos P. Interleukin 4 and tumour necrosis factor alpha induce different adhesion pathways in endothelial cells for the binding of peripheral blood lymphocytes. Scand J Immunol. 1992 Oct;36(4):575–585. doi: 10.1111/j.1365-3083.1992.tb03226.x. [DOI] [PubMed] [Google Scholar]
  23. Gauchat J. F., Henchoz S., Mazzei G., Aubry J. P., Brunner T., Blasey H., Life P., Talabot D., Flores-Romo L., Thompson J. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature. 1993 Sep 23;365(6444):340–343. doi: 10.1038/365340a0. [DOI] [PubMed] [Google Scholar]
  24. Gerondakis S. Structure and expression of murine germ-line immunoglobulin epsilon heavy chain transcripts induced by interleukin 4. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1581–1585. doi: 10.1073/pnas.87.4.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gosset P., Tsicopoulos A., Wallaert B., Joseph M., Capron A., Tonnel A. B. Tumor necrosis factor alpha and interleukin-6 production by human mononuclear phagocytes from allergic asthmatics after IgE-dependent stimulation. Am Rev Respir Dis. 1992 Sep;146(3):768–774. doi: 10.1164/ajrccm/146.3.768. [DOI] [PubMed] [Google Scholar]
  26. Hauser I. A., Johnson D. R., Madri J. A. Differential induction of VCAM-1 on human iliac venous and arterial endothelial cells and its role in adhesion. J Immunol. 1993 Nov 15;151(10):5172–5185. [PubMed] [Google Scholar]
  27. Iademarco M. F., McQuillan J. J., Rosen G. D., Dean D. C. Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem. 1992 Aug 15;267(23):16323–16329. [PubMed] [Google Scholar]
  28. Kips J. C., Tavernier J. H., Joos G. F., Peleman R. A., Pauwels R. A. The potential role of tumour necrosis factor alpha in asthma. Clin Exp Allergy. 1993 Apr;23(4):247–250. doi: 10.1111/j.1365-2222.1993.tb00317.x. [DOI] [PubMed] [Google Scholar]
  29. Kotanides H., Reich N. C. Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science. 1993 Nov 19;262(5137):1265–1267. doi: 10.1126/science.7694370. [DOI] [PubMed] [Google Scholar]
  30. Lukacs N. W., Strieter R. M., Chensue S. W., Kunkel S. L. Interleukin-4-dependent pulmonary eosinophil infiltration in a murine model of asthma. Am J Respir Cell Mol Biol. 1994 May;10(5):526–532. doi: 10.1165/ajrcmb.10.5.8179915. [DOI] [PubMed] [Google Scholar]
  31. Masinovsky B., Urdal D., Gallatin W. M. IL-4 acts synergistically with IL-1 beta to promote lymphocyte adhesion to microvascular endothelium by induction of vascular cell adhesion molecule-1. J Immunol. 1990 Nov 1;145(9):2886–2895. [PubMed] [Google Scholar]
  32. Montefort S., Feather I. H., Wilson S. J., Haskard D. O., Lee T. H., Holgate S. T., Howarth P. H. The expression of leukocyte-endothelial adhesion molecules is increased in perennial allergic rhinitis. Am J Respir Cell Mol Biol. 1992 Oct;7(4):393–398. doi: 10.1165/ajrcmb/7.4.393. [DOI] [PubMed] [Google Scholar]
  33. Montgomery K. F., Osborn L., Hession C., Tizard R., Goff D., Vassallo C., Tarr P. I., Bomsztyk K., Lobb R., Harlan J. M. Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6523–6527. doi: 10.1073/pnas.88.15.6523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Moser R., Groscurth P., Carballido J. M., Bruijnzeel P. L., Blaser K., Heusser C. H., Fehr J. Interleukin-4 induces tissue eosinophilia in mice: correlation with its in vitro capacity to stimulate the endothelial cell-dependent selective transmigration of human eosinophils. J Lab Clin Med. 1993 Nov;122(5):567–575. [PubMed] [Google Scholar]
  35. Nakajima H., Sano H., Nishimura T., Yoshida S., Iwamoto I. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J Exp Med. 1994 Apr 1;179(4):1145–1154. doi: 10.1084/jem.179.4.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nelson R. M., Dolich S., Aruffo A., Cecconi O., Bevilacqua M. P. Higher-affinity oligosaccharide ligands for E-selectin. J Clin Invest. 1993 Mar;91(3):1157–1166. doi: 10.1172/JCI116275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Paleolog E. M., Aluri G. R., Feldmann M. Contrasting effects of interferon gamma and interleukin 4 on responses of human vascular endothelial cells to tumour necrosis factor alpha. Cytokine. 1992 Nov;4(6):470–478. doi: 10.1016/1043-4666(92)90007-e. [DOI] [PubMed] [Google Scholar]
  38. Postlethwaite A. E., Holness M. A., Katai H., Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest. 1992 Oct;90(4):1479–1485. doi: 10.1172/JCI116015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Read M. A., Whitley M. Z., Williams A. J., Collins T. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med. 1994 Feb 1;179(2):503–512. doi: 10.1084/jem.179.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Renkonen R., Mattila P., Majuri M. L., Paavonen T., Silvennoinen O. IL-4 decreases IFN-gamma-induced endothelial ICAM-1 expression by a transcriptional mechanism. Scand J Immunol. 1992 May;35(5):525–530. doi: 10.1111/j.1365-3083.1992.tb03251.x. [DOI] [PubMed] [Google Scholar]
  41. Rice G. E., Munro J. M., Corless C., Bevilacqua M. P. Vascular and nonvascular expression of INCAM-110. A target for mononuclear leukocyte adhesion in normal and inflamed human tissues. Am J Pathol. 1991 Feb;138(2):385–393. [PMC free article] [PubMed] [Google Scholar]
  42. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  43. Rosen G. D., Sanes J. R., LaChance R., Cunningham J. M., Roman J., Dean D. C. Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis. Cell. 1992 Jun 26;69(7):1107–1119. doi: 10.1016/0092-8674(92)90633-n. [DOI] [PubMed] [Google Scholar]
  44. Rothman P., Li S. C., Gorham B., Glimcher L., Alt F., Boothby M. Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. Mol Cell Biol. 1991 Nov;11(11):5551–5561. doi: 10.1128/mcb.11.11.5551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rüegg C., Postigo A. A., Sikorski E. E., Butcher E. C., Pytela R., Erle D. J. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol. 1992 Apr;117(1):179–189. doi: 10.1083/jcb.117.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schwarz E. M., Salgame P., Bloom B. R. Molecular regulation of human interleukin 2 and T-cell function by interleukin 4. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7734–7738. doi: 10.1073/pnas.90.16.7734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  48. Standiford T. J., Kunkel S. L., Liebler J. M., Burdick M. D., Gilbert A. R., Strieter R. M. Gene expression of macrophage inflammatory protein-1 alpha from human blood monocytes and alveolar macrophages is inhibited by interleukin-4. Am J Respir Cell Mol Biol. 1993 Aug;9(2):192–198. doi: 10.1165/ajrcmb/9.2.192. [DOI] [PubMed] [Google Scholar]
  49. Staunton D. E., Marlin S. D., Stratowa C., Dustin M. L., Springer T. A. Primary structure of ICAM-1 demonstrates interaction between members of the immunoglobulin and integrin supergene families. Cell. 1988 Mar 25;52(6):925–933. doi: 10.1016/0092-8674(88)90434-5. [DOI] [PubMed] [Google Scholar]
  50. Tepper R. I., Levinson D. A., Stanger B. Z., Campos-Torres J., Abbas A. K., Leder P. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990 Aug 10;62(3):457–467. doi: 10.1016/0092-8674(90)90011-3. [DOI] [PubMed] [Google Scholar]
  51. Thornhill M. H., Kyan-Aung U., Haskard D. O. IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils. J Immunol. 1990 Apr 15;144(8):3060–3065. [PubMed] [Google Scholar]
  52. Thornhill M. H., Wellicome S. M., Mahiouz D. L., Lanchbury J. S., Kyan-Aung U., Haskard D. O. Tumor necrosis factor combines with IL-4 or IFN-gamma to selectively enhance endothelial cell adhesiveness for T cells. The contribution of vascular cell adhesion molecule-1-dependent and -independent binding mechanisms. J Immunol. 1991 Jan 15;146(2):592–598. [PubMed] [Google Scholar]
  53. Verdegaal E. M., Beekhuizen H., Blokland I., van Furth R. Increased adhesion of human monocytes to IL-4-stimulated human venous endothelial cells via CD11/CD18, and very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1)-dependent mechanisms. Clin Exp Immunol. 1993 Aug;93(2):292–298. doi: 10.1111/j.1365-2249.1993.tb07982.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Walker C., Bode E., Boer L., Hansel T. T., Blaser K., Virchow J. C., Jr Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992 Jul;146(1):109–115. doi: 10.1164/ajrccm/146.1.109. [DOI] [PubMed] [Google Scholar]
  55. Wong H. L., Costa G. L., Lotze M. T., Wahl S. M. Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo. J Exp Med. 1993 Mar 1;177(3):775–781. doi: 10.1084/jem.177.3.775. [DOI] [PMC free article] [PubMed] [Google Scholar]

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