Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Mar 15;101(6):1261–1272. doi: 10.1172/JCI1986

Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo.

N Oppenheimer-Marks 1, R I Brezinschek 1, M Mohamadzadeh 1, R Vita 1, P E Lipsky 1
PMCID: PMC508680  PMID: 9502767

Abstract

The capacity of endothelial cells (EC) to produce IL-15 and the capacity of IL-15 to influence transendothelial migration of T cells was examined. Human umbilical vein endothelial cells expressed both IL-15 mRNA and protein. Moreover, endothelial-derived IL-15 enhanced transendothelial migration of T cells as evidenced by the inhibition of this process by blocking monoclonal antibodies to IL-15. IL-15 enhanced transendothelial migration of T cells by activating the binding capacity of the integrin adhesion molecule LFA-1 (CD11a/CD18) and also increased T cell motility. In addition, IL-15 induced expression of the early activation molecule CD69. The importance of IL-15 in regulating migration of T cells in vivo was documented by its capacity to enhance accumulation of adoptively transferred human T cells in rheumatoid arthritis synovial tissue engrafted into immune deficient SCID mice. These results demonstrate that EC produce IL-15 and imply that endothelial IL-15 plays a critical role in stimulation of T cells to extravasate into inflammatory tissue.

Full Text

The Full Text of this article is available as a PDF (516.4 KB).

Selected References

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

  1. Allavena P., Giardina G., Bianchi G., Mantovani A. IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. J Leukoc Biol. 1997 Jun;61(6):729–735. doi: 10.1002/jlb.61.6.729. [DOI] [PubMed] [Google Scholar]
  2. Assenmacher M., Scheffold A., Schmitz J., Segura Checa J. A., Miltenyi S., Radbruch A. Specific expression of surface interferon-gamma on interferon-gamma producing T cells from mouse and man. Eur J Immunol. 1996 Jan;26(1):263–267. doi: 10.1002/eji.1830260141. [DOI] [PubMed] [Google Scholar]
  3. Brezinschek R. I., Brezinschek H. P., Lazarovits A. I., Lipsky P. E., Oppenheimer-Marks N. Expression of the beta 7 integrin by human endothelial cells. Am J Pathol. 1996 Nov;149(5):1651–1660. [PMC free article] [PubMed] [Google Scholar]
  4. Brezinschek R. I., Lipsky P. E., Galea P., Vita R., Oppenheimer-Marks N. Phenotypic characterization of CD4+ T cells that exhibit a transendothelial migratory capacity. J Immunol. 1995 Apr 1;154(7):3062–3077. [PubMed] [Google Scholar]
  5. Carr M. W., Alon R., Springer T. A. The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. Immunity. 1996 Feb;4(2):179–187. doi: 10.1016/s1074-7613(00)80682-2. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Carson W. E., Giri J. G., Lindemann M. J., Linett M. L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M. A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. doi: 10.1084/jem.180.4.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cush J. J., Lipsky P. E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. doi: 10.1002/art.1780311003. [DOI] [PubMed] [Google Scholar]
  9. Damle N. K., Aruffo A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6403–6407. doi: 10.1073/pnas.88.15.6403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dustin M. L., Springer T. A. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature. 1989 Oct 19;341(6243):619–624. doi: 10.1038/341619a0. [DOI] [PubMed] [Google Scholar]
  11. Geiler T., Kriegsmann J., Keyszer G. M., Gay R. E., Gay S. A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum. 1994 Nov;37(11):1664–1671. doi: 10.1002/art.1780371116. [DOI] [PubMed] [Google Scholar]
  12. Geppert T. D., Lipsky P. E. Antigen presentation by cells that are not of bone marrow origin. Reg Immunol. 1989 Jan-Feb;2(1):60–71. [PubMed] [Google Scholar]
  13. Gimbrone M. A., Jr, Obin M. S., Brock A. F., Luis E. A., Hass P. E., Hébert C. A., Yip Y. K., Leung D. W., Lowe D. G., Kohr W. J. Endothelial interleukin-8: a novel inhibitor of leukocyte-endothelial interactions. Science. 1989 Dec 22;246(4937):1601–1603. doi: 10.1126/science.2688092. [DOI] [PubMed] [Google Scholar]
  14. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Giri J. G., Anderson D. M., Kumaki S., Park L. S., Grabstein K. H., Cosman D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol. 1995 May;57(5):763–766. doi: 10.1002/jlb.57.5.763. [DOI] [PubMed] [Google Scholar]
  16. Giri J. G., Kumaki S., Ahdieh M., Friend D. J., Loomis A., Shanebeck K., DuBose R., Cosman D., Park L. S., Anderson D. M. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J. 1995 Aug 1;14(15):3654–3663. doi: 10.1002/j.1460-2075.1995.tb00035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  18. Jorgensen C., Couret I., Canovas F., Bologna C., Brochier J., Reme T., Lipsky P., Sany J. Mononuclear cell retention in rheumatoid synovial tissue engrafted in severe combined immunodeficient (SCID) mice is up-regulated by tumour necrosis factor-alpha (TNF-alpha) and mediated through intercellular adhesion molecule-1 (ICAM-1). Clin Exp Immunol. 1996 Oct;106(1):20–25. [PubMed] [Google Scholar]
  19. Jorgensen C., Couret I., Hellier I., Bologna C., Canovas F., Brochier J., Reme T., Sany J. In vivo migration of radiolabelled lymphocytes in rheumatoid synovial tissue engrafted in SCID mice: implication of beta 2 and beta 7-integrin. J Rheumatol. 1996 Jan;23(1):32–35. [PubMed] [Google Scholar]
  20. Kaplan D. R., Bergmann C. A., Gould D., Landmeier B. Membrane-associated interleukin 2 epitopes on the surface of human T lymphocytes. J Immunol. 1988 Feb 1;140(3):819–826. [PubMed] [Google Scholar]
  21. Karmann K., Hughes C. C., Schechner J., Fanslow W. C., Pober J. S. CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4342–4346. doi: 10.1073/pnas.92.10.4342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kennedy M. K., Park L. S. Characterization of interleukin-15 (IL-15) and the IL-15 receptor complex. J Clin Immunol. 1996 May;16(3):134–143. doi: 10.1007/BF01540911. [DOI] [PubMed] [Google Scholar]
  23. Kohem C. L., Brezinschek R. I., Wisbey H., Tortorella C., Lipsky P. E., Oppenheimer-Marks N. Enrichment of differentiated CD45RBdim,CD27- memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 1996 May;39(5):844–854. doi: 10.1002/art.1780390518. [DOI] [PubMed] [Google Scholar]
  24. Li Y. S., Shyy Y. J., Wright J. G., Valente A. J., Cornhill J. F., Kolattukudy P. E. The expression of monocyte chemotactic protein (MCP-1) in human vascular endothelium in vitro and in vivo. Mol Cell Biochem. 1993 Sep 8;126(1):61–68. doi: 10.1007/BF01772208. [DOI] [PubMed] [Google Scholar]
  25. Lipsky P. E., Davis L. S., Cush J. J., Oppenheimer-Marks N. The role of cytokines in the pathogenesis of rheumatoid arthritis. Springer Semin Immunopathol. 1989;11(2):123–162. doi: 10.1007/BF00197186. [DOI] [PubMed] [Google Scholar]
  26. Mach F., Schönbeck U., Sukhova G. K., Bourcier T., Bonnefoy J. Y., Pober J. S., Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1931–1936. doi: 10.1073/pnas.94.5.1931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McInnes I. B., Leung B. P., Sturrock R. D., Field M., Liew F. Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med. 1997 Feb;3(2):189–195. doi: 10.1038/nm0297-189. [DOI] [PubMed] [Google Scholar]
  28. McInnes I. B., al-Mughales J., Field M., Leung B. P., Huang F. P., Dixon R., Sturrock R. D., Wilkinson P. C., Liew F. Y. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996 Feb;2(2):175–182. doi: 10.1038/nm0296-175. [DOI] [PubMed] [Google Scholar]
  29. Müller-Ladner U., Kriegsmann J., Franklin B. N., Matsumoto S., Geiler T., Gay R. E., Gay S. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996 Nov;149(5):1607–1615. [PMC free article] [PubMed] [Google Scholar]
  30. Nieto M., del Pozo M. A., Sánchez-Madrid F. Interleukin-15 induces adhesion receptor redistribution in T lymphocytes. Eur J Immunol. 1996 Jun;26(6):1302–1307. doi: 10.1002/eji.1830260619. [DOI] [PubMed] [Google Scholar]
  31. Onu A., Pohl T., Krause H., Bulfone-Paus S. Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms. J Immunol. 1997 Jan 1;158(1):255–262. [PubMed] [Google Scholar]
  32. Oppenheimer-Marks N., Davis L. S., Bogue D. T., Ramberg J., Lipsky P. E. Differential utilization of ICAM-1 and VCAM-1 during the adhesion and transendothelial migration of human T lymphocytes. J Immunol. 1991 Nov 1;147(9):2913–2921. [PubMed] [Google Scholar]
  33. Oppenheimer-Marks N., Davis L. S., Lipsky P. E. Human T lymphocyte adhesion to endothelial cells and transendothelial migration. Alteration of receptor use relates to the activation status of both the T cell and the endothelial cell. J Immunol. 1990 Jul 1;145(1):140–148. [PubMed] [Google Scholar]
  34. Oppenheimer-Marks N., Ziff M. Migration of lymphocytes through endothelial cell monolayers: augmentation by interferon-gamma. Cell Immunol. 1988 Jul;114(2):307–323. doi: 10.1016/0008-8749(88)90324-3. [DOI] [PubMed] [Google Scholar]
  35. Rendt K. E., Barry T. S., Jones D. M., Richter C. B., McCachren S. S., Haynes B. F. Engraftment of human synovium into severe combined immune deficient mice. Migration of human peripheral blood T cells to engrafted human synovium and to mouse lymph nodes. J Immunol. 1993 Dec 15;151(12):7324–7336. [PubMed] [Google Scholar]
  36. Roth S. J., Carr M. W., Springer T. A. C-C chemokines, but not the C-X-C chemokines interleukin-8 and interferon-gamma inducible protein-10, stimulate transendothelial chemotaxis of T lymphocytes. Eur J Immunol. 1995 Dec;25(12):3482–3488. doi: 10.1002/eji.1830251241. [DOI] [PubMed] [Google Scholar]
  37. Rothlein R., Mainolfi E. A., Czajkowski M., Marlin S. D. A form of circulating ICAM-1 in human serum. J Immunol. 1991 Dec 1;147(11):3788–3793. [PubMed] [Google Scholar]
  38. Sharar S. R., Winn R. K., Harlan J. M. The adhesion cascade and anti-adhesion therapy: an overview. Springer Semin Immunopathol. 1995;16(4):359–378. doi: 10.1007/BF00196093. [DOI] [PubMed] [Google Scholar]
  39. Tagaya Y., Bamford R. N., DeFilippis A. P., Waldmann T. A. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity. 1996 Apr;4(4):329–336. doi: 10.1016/s1074-7613(00)80246-0. [DOI] [PubMed] [Google Scholar]
  40. Tagaya Y., Burton J. D., Miyamoto Y., Waldmann T. A. Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. EMBO J. 1996 Sep 16;15(18):4928–4939. [PMC free article] [PubMed] [Google Scholar]
  41. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  42. Wilkinson P. C., Liew F. Y. Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med. 1995 Mar 1;181(3):1255–1259. doi: 10.1084/jem.181.3.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. de Jong J. L., Farner N. L., Widmer M. B., Giri J. G., Sondel P. M. Interaction of IL-15 with the shared IL-2 receptor beta and gamma c subunits. The IL-15/beta/gamma c receptor-ligand complex is less stable than the IL-2/beta/gamma c receptor-ligand complex. J Immunol. 1996 Feb 15;156(4):1339–1348. [PubMed] [Google Scholar]
  44. del Pozo M. A., Sánchez-Mateos P., Nieto M., Sánchez-Madrid F. Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. J Cell Biol. 1995 Oct;131(2):495–508. doi: 10.1083/jcb.131.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES