Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1997 Jul;91(3):450–457. doi: 10.1046/j.1365-2567.1997.00263.x

Interleukin-13 selectively induces monocyte chemoattractant protein-1 synthesis and secretion by human endothelial cells. Involvement of IL-4R alpha and Stat6 phosphorylation.

M Goebeler 1, B Schnarr 1, A Toksoy 1, M Kunz 1, E B Bröcker 1, A Duschl 1, R Gillitzer 1
PMCID: PMC1364016  PMID: 9301536

Abstract

Chemokines secreted by endothelium have been demonstrated to promote leucocyte recruitment to sites of inflammation. In the present study we investigated the effect of the T lymphocyte-secreted cytokine interleukin (IL)-13 on endothelial expression of chemokines. Employing in situ hybridization and enzyme-linked immunosorbent assay (ELISA) techniques we demonstrate that IL-13, which shares many of its activities with IL-4, selectively induces expression of the C-C chemokine monocyte chemoattractant protein (MCP)-1 in human umbilical vein endothelial cells (HUVEC). However, it fails to up-regulate other C-C and C-X-C chemokines potentially inducible in endothelium such as RANTES (regulated on activation, normal T expressed and secreted), gro-alpha, or IL-8. IL-13 dose-dependently induces monocyte chemotactic activity by HUVEC which can be efficiently blocked by neutralizing antisera against MCP-1. In contrast to the synergistic effect of IL-13 and tumour necrosis factor-alpha (TNF-alpha) on endothelial vascular cell adhesion molecule-1 (VCAM-1) surface expression, TNF-alpha-induced secretion of MCP-1 is not augmented by IL-13. Studying the signalling pathway activated by IL-13 it is demonstrated that a neutralizing monoclonal antibody (mAb) to the 140,000 MW component of the IL-4 receptor (IL-4R alpha) inhibits the effect of IL-13. Immunoprecipitation studies reveal that endothelial IL-4R alpha is rapidly tyrosine phosphorylated upon treatment with IL-13 and IL-4. We furthermore show that both cytokines activate the signal transducer and activator of transcription (Stat) protein-6 in endothelial cells. Our data suggest that IL-13 partly utilizes components of the IL-4 receptor signalling pathway for induction of endothelial MCP-1 expression to facilitate recruitment of blood leucocytes.

Full text

PDF
450

Images in this article

453Figure 3
on p.453
455Figure 6
on p.455
455Figure 7
on p.455

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  2. Beekhuizen H., van Furth R. Monocyte adherence to human vascular endothelium. J Leukoc Biol. 1993 Oct;54(4):363–378. [PubMed] [Google Scholar]
  3. Bochner B. S., Klunk D. A., Sterbinsky S. A., Coffman R. L., Schleimer R. P. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol. 1995 Jan 15;154(2):799–803. [PubMed] [Google Scholar]
  4. Callard R. E., Matthews D. J., Hibbert L. IL-4 and IL-13 receptors: are they one and the same? Immunol Today. 1996 Mar;17(3):108–110. doi: 10.1016/0167-5699(96)80600-1. [DOI] [PubMed] [Google Scholar]
  5. Caput D., Laurent P., Kaghad M., Lelias J. M., Lefort S., Vita N., Ferrara P. Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain. J Biol Chem. 1996 Jul 12;271(28):16921–16926. doi: 10.1074/jbc.271.28.16921. [DOI] [PubMed] [Google Scholar]
  6. Carlos T. M., Schwartz B. R., Kovach N. L., Yee E., Rosa M., Osborn L., Chi-Rosso G., Newman B., Lobb R., Rosso M. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood. 1990 Sep 1;76(5):965–970. [PubMed] [Google Scholar]
  7. Carr M. W., Roth S. J., Luther E., Rose S. S., Springer T. A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652–3656. doi: 10.1073/pnas.91.9.3652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chuluyan H. E., Schall T. J., Yoshimura T., Issekutz A. C. IL-1 activation of endothelium supports VLA-4 (CD49d/CD29)-mediated monocyte transendothelial migration to C5a, MIP-1 alpha, RANTES, and PAF but inhibits migration to MCP-1: a regulatory role for endothelium-derived MCP-1. J Leukoc Biol. 1995 Jul;58(1):71–79. doi: 10.1002/jlb.58.1.71. [DOI] [PubMed] [Google Scholar]
  9. Cosentino G., Soprana E., Thienes C. P., Siccardi A. G., Viale G., Vercelli D. IL-13 down-regulates CD14 expression and TNF-alpha secretion in normal human monocytes. J Immunol. 1995 Sep 15;155(6):3145–3151. [PubMed] [Google Scholar]
  10. Doherty T. M., Kastelein R., Menon S., Andrade S., Coffman R. L. Modulation of murine macrophage function by IL-13. J Immunol. 1993 Dec 15;151(12):7151–7160. [PubMed] [Google Scholar]
  11. Doyle A. G., Herbein G., Montaner L. J., Minty A. J., Caput D., Ferrara P., Gordon S. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-gamma. Eur J Immunol. 1994 Jun;24(6):1441–1445. doi: 10.1002/eji.1830240630. [DOI] [PubMed] [Google Scholar]
  12. Furie M. B., Randolph G. J. Chemokines and tissue injury. Am J Pathol. 1995 Jun;146(6):1287–1301. [PMC free article] [PubMed] [Google Scholar]
  13. Goebeler M., Roth J., Bröcker E. B., Sorg C., Schulze-Osthoff K. Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt. J Immunol. 1995 Sep 1;155(5):2459–2467. [PubMed] [Google Scholar]
  14. He Y. W., Malek T. R. The IL-2 receptor gamma c chain does not function as a subunit shared by the IL-4 and IL-13 receptors. Implication for the structure of the IL-4 receptor. J Immunol. 1995 Jul 1;155(1):9–12. [PubMed] [Google Scholar]
  15. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M., McKnight S. L. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. doi: 10.1126/science.8085155. [DOI] [PubMed] [Google Scholar]
  16. Iademarco M. F., Barks J. L., Dean D. C. Regulation of vascular cell adhesion molecule-1 expression by IL-4 and TNF-alpha in cultured endothelial cells. J Clin Invest. 1995 Jan;95(1):264–271. doi: 10.1172/JCI117650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ihle J. N., Kerr I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995 Feb;11(2):69–74. doi: 10.1016/s0168-9525(00)89000-9. [DOI] [PubMed] [Google Scholar]
  18. Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K., Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  19. Kruse N., Tony H. P., Sebald W. Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement. EMBO J. 1992 Sep;11(9):3237–3244. doi: 10.1002/j.1460-2075.1992.tb05401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lin J. X., Migone T. S., Tsang M., Friedmann M., Weatherbee J. A., Zhou L., Yamauchi A., Bloom E. T., Mietz J., John S. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995 Apr;2(4):331–339. doi: 10.1016/1074-7613(95)90141-8. [DOI] [PubMed] [Google Scholar]
  21. Mantovani A., Bussolino F., Dejana E. Cytokine regulation of endothelial cell function. FASEB J. 1992 May;6(8):2591–2599. doi: 10.1096/fasebj.6.8.1592209. [DOI] [PubMed] [Google Scholar]
  22. Marfaing-Koka A., Devergne O., Gorgone G., Portier A., Schall T. J., Galanaud P., Emilie D. Regulation of the production of the RANTES chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and inhibition by IL-4 and IL-13. J Immunol. 1995 Feb 15;154(4):1870–1878. [PubMed] [Google Scholar]
  23. 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]
  24. McKenzie A. N., Culpepper J. A., de Waal Malefyt R., Brière F., Punnonen J., Aversa G., Sato A., Dang W., Cocks B. G., Menon S. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3735–3739. doi: 10.1073/pnas.90.8.3735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Meerschaert J., Furie M. B. The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18, and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium. J Immunol. 1995 Apr 15;154(8):4099–4112. [PubMed] [Google Scholar]
  26. Obiri N. I., Debinski W., Leonard W. J., Puri R. K. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem. 1995 Apr 14;270(15):8797–8804. doi: 10.1074/jbc.270.15.8797. [DOI] [PubMed] [Google Scholar]
  27. Palmer-Crocker R. L., Hughes C. C., Pober J. S. IL-4 and IL-13 activate the JAK2 tyrosine kinase and Stat6 in cultured human vascular endothelial cells through a common pathway that does not involve the gamma c chain. J Clin Invest. 1996 Aug 1;98(3):604–609. doi: 10.1172/JCI118829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Palmer-Crocker R. L., Pober J. S. IL-4 induction of VCAM-1 on endothelial cells involves activation of a protein tyrosine kinase. J Immunol. 1995 Mar 15;154(6):2838–2845. [PubMed] [Google Scholar]
  29. Randolph G. J., Furie M. B. A soluble gradient of endogenous monocyte chemoattractant protein-1 promotes the transendothelial migration of monocytes in vitro. J Immunol. 1995 Oct 1;155(7):3610–3618. [PubMed] [Google Scholar]
  30. Ritter U., Moll H., Laskay T., Bröcker E., Velazco O., Becker I., Gillitzer R. Differential expression of chemokines in patients with localized and diffuse cutaneous American leishmaniasis. J Infect Dis. 1996 Mar;173(3):699–709. doi: 10.1093/infdis/173.3.699. [DOI] [PubMed] [Google Scholar]
  31. Rollins B. J., Pober J. S. Interleukin-4 induces the synthesis and secretion of MCP-1/JE by human endothelial cells. Am J Pathol. 1991 Jun;138(6):1315–1319. [PMC free article] [PubMed] [Google Scholar]
  32. Schleimer R. P., Sterbinsky S. A., Kaiser J., Bickel C. A., Klunk D. A., Tomioka K., Newman W., Luscinskas F. W., Gimbrone M. A., Jr, McIntyre B. W. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol. 1992 Feb 15;148(4):1086–1092. [PubMed] [Google Scholar]
  33. Schnyder B., Lugli S., Feng N., Etter H., Lutz R. A., Ryffel B., Sugamura K., Wunderli-Allenspach H., Moser R. Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain. Blood. 1996 May 15;87(10):4286–4295. [PubMed] [Google Scholar]
  34. Sica A., Wang J. M., Colotta F., Dejana E., Mantovani A., Oppenheim J. J., Larsen C. G., Zachariae C. O., Matsushima K. Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor. J Immunol. 1990 Apr 15;144(8):3034–3038. [PubMed] [Google Scholar]
  35. Sironi M., Sciacca F. L., Matteucci C., Conni M., Vecchi A., Bernasconi S., Minty A., Caput D., Ferrara P., Colotta F. Regulation of endothelial and mesothelial cell function by interleukin-13: selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production. Blood. 1994 Sep 15;84(6):1913–1921. [PubMed] [Google Scholar]
  36. Smerz-Bertling C., Duschl A. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. J Biol Chem. 1995 Jan 13;270(2):966–970. doi: 10.1074/jbc.270.2.966. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Taub D. D., Lloyd A. R., Conlon K., Wang J. M., Ortaldo J. R., Harada A., Matsushima K., Kelvin D. J., Oppenheim J. J. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med. 1993 Jun 1;177(6):1809–1814. doi: 10.1084/jem.177.6.1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. Tony H. P., Shen B. J., Reusch P., Sebald W. Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency. Eur J Biochem. 1994 Oct 15;225(2):659–665. doi: 10.1111/j.1432-1033.1994.00659.x. [DOI] [PubMed] [Google Scholar]
  42. Vita N., Lefort S., Laurent P., Caput D., Ferrara P. Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types. J Biol Chem. 1995 Feb 24;270(8):3512–3517. doi: 10.1074/jbc.270.8.3512. [DOI] [PubMed] [Google Scholar]
  43. Zurawski G., de Vries J. E. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. doi: 10.1016/0167-5699(94)90021-3. [DOI] [PubMed] [Google Scholar]
  44. Zurawski S. M., Vega F., Jr, Huyghe B., Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993 Jul;12(7):2663–2670. doi: 10.1002/j.1460-2075.1993.tb05927.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. de Waal Malefyt R., Figdor C. G., Huijbens R., Mohan-Peterson S., Bennett B., Culpepper J., Dang W., Zurawski G., de Vries J. E. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol. 1993 Dec 1;151(11):6370–6381. [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES