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. 1991 Jun 1;173(6):1493–1500. doi: 10.1084/jem.173.6.1493

Endothelial-leukocyte adhesion molecule 1 stimulates the adhesive activity of leukocyte integrin CR3 (CD11b/CD18, Mac-1, alpha m beta 2) on human neutrophils

PMCID: PMC2190843  PMID: 1709677

Abstract

Two classes of adhesion molecules have well-defined roles in the attachment of unstimulated polymorphonuclear leukocytes (PMN) to cytokine-treated endothelial cells. Endothelial-leukocyte adhesion molecule 1 (ELAM-1) on endothelial cells interacts with specific carbohydrate residues on the PMN, and the leukocyte integrins (CD18 antigens) on PMN interact with intracellular adhesion molecule 1 and other structures on endothelium. Here we show that these two classes of molecules can act sequentially in an "adhesion cascade". Interaction of PMN with ELAM-1-bearing endothelial cells causes PMN to express enhanced adhesive activity of the integrin CR3 (CD11b/CD18). Expression of ELAM-1 on the cytokine-treated endothelium appears both necessary and sufficient for the stimulation of CR3 activity since blockade of ELAM-1 with mAbs prevents the activation of CR3 by cytokine-treated endothelium, and immobilized recombinant ELAM-1 activates CR3. The ability to activate CR3 is shared by chemattractants, suggesting that ELAM-1 may serve as a "tethered chemattractant." This hypothesis is strengthened by the observation that recombinant soluble ELAM-1 directs movement of PMN in chemotaxis chambers. These results suggest a mechanism by which multiple adhesive molecules may function together in diapedesis. ELAM-1 serves both as an adhesin and as a trigger that recruits the participation of additional adhesion molecules. Our results also suggest that ligands for adhesion molecules may also be "receptors" capable of generating intracellular signals.

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Selected References

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  1. Altieri D. C., Edgington T. S. The saturable high affinity association of factor X to ADP-stimulated monocytes defines a novel function of the Mac-1 receptor. J Biol Chem. 1988 May 25;263(15):7007–7015. [PubMed] [Google Scholar]
  2. Arfors K. E., Lundberg C., Lindbom L., Lundberg K., Beatty P. G., Harlan J. M. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood. 1987 Jan;69(1):338–340. [PubMed] [Google Scholar]
  3. Barsoum J. Introduction of stable high-copy-number DNA into Chinese hamster ovary cells by electroporation. DNA Cell Biol. 1990 May;9(4):293–300. doi: 10.1089/dna.1990.9.293. [DOI] [PubMed] [Google Scholar]
  4. Benjamin C., Dougas I., Chi-Rosso G., Luhowskyj S., Rosa M., Newman B., Osborn L., Vassallo C., Hession C., Goelz S. A blocking monoclonal antibody to endothelial-leukocyte adhesion molecule-1 (ELAM1). Biochem Biophys Res Commun. 1990 Aug 31;171(1):348–353. doi: 10.1016/0006-291x(90)91400-m. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  7. Buyon J. P., Abramson S. B., Philips M. R., Slade S. G., Ross G. D., Weissmann G., Winchester R. J. Dissociation between increased surface expression of gp165/95 and homotypic neutrophil aggregation. J Immunol. 1988 May 1;140(9):3156–3160. [PubMed] [Google Scholar]
  8. Detmers P. A., Lo S. K., Olsen-Egbert E., Walz A., Baggiolini M., Cohn Z. A. Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J Exp Med. 1990 Apr 1;171(4):1155–1162. doi: 10.1084/jem.171.4.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Deuel T. F., Senior R. M., Huang J. S., Griffin G. L. Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest. 1982 Apr;69(4):1046–1049. doi: 10.1172/JCI110509. [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. English D., Andersen B. R. Single-step separation of red blood cells. Granulocytes and mononuclear leukocytes on discontinuous density gradients of Ficoll-Hypaque. J Immunol Methods. 1974 Aug;5(3):249–252. doi: 10.1016/0022-1759(74)90109-4. [DOI] [PubMed] [Google Scholar]
  12. Fleit H. B., Wright S. D., Unkeless J. C. Human neutrophil Fc gamma receptor distribution and structure. Proc Natl Acad Sci U S A. 1982 May;79(10):3275–3279. doi: 10.1073/pnas.79.10.3275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Furie M. B., McHugh D. D. Migration of neutrophils across endothelial monolayers is stimulated by treatment of the monolayers with interleukin-1 or tumor necrosis factor-alpha. J Immunol. 1989 Nov 15;143(10):3309–3317. [PubMed] [Google Scholar]
  14. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Geng J. G., Bevilacqua M. P., Moore K. L., McIntyre T. M., Prescott S. M., Kim J. M., Bliss G. A., Zimmerman G. A., McEver R. P. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature. 1990 Feb 22;343(6260):757–760. doi: 10.1038/343757a0. [DOI] [PubMed] [Google Scholar]
  16. Harlan J. M., Killen P. D., Senecal F. M., Schwartz B. R., Yee E. K., Taylor R. F., Beatty P. G., Price T. H., Ochs H. D. The role of neutrophil membrane glycoprotein GP-150 in neutrophil adherence to endothelium in vitro. Blood. 1985 Jul;66(1):167–178. [PubMed] [Google Scholar]
  17. Hession C., Osborn L., Goff D., Chi-Rosso G., Vassallo C., Pasek M., Pittack C., Tizard R., Goelz S., McCarthy K. Endothelial leukocyte adhesion molecule 1: direct expression cloning and functional interactions. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1673–1677. doi: 10.1073/pnas.87.5.1673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lawrence M. B., Smith C. W., Eskin S. G., McIntire L. V. Effect of venous shear stress on CD18-mediated neutrophil adhesion to cultured endothelium. Blood. 1990 Jan 1;75(1):227–237. [PubMed] [Google Scholar]
  19. Lo S. K., Detmers P. A., Levin S. M., Wright S. D. Transient adhesion of neutrophils to endothelium. J Exp Med. 1989 May 1;169(5):1779–1793. doi: 10.1084/jem.169.5.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lo S. K., Van Seventer G. A., Levin S. M., Wright S. D. Two leukocyte receptors (CD11a/CD18 and CD11b/CD18) mediate transient adhesion to endothelium by binding to different ligands. J Immunol. 1989 Nov 15;143(10):3325–3329. [PubMed] [Google Scholar]
  21. Lowe J. B., Stoolman L. M., Nair R. P., Larsen R. D., Berhend T. L., Marks R. M. ELAM-1--dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltransferase cDNA. Cell. 1990 Nov 2;63(3):475–484. doi: 10.1016/0092-8674(90)90444-j. [DOI] [PubMed] [Google Scholar]
  22. Lundberg C., Wright S. D. Relation of the CD11/CD18 family of leukocyte antigens to the transient neutropenia caused by chemoattractants. Blood. 1990 Sep 15;76(6):1240–1245. [PubMed] [Google Scholar]
  23. Moser R., Schleiffenbaum B., Groscurth P., Fehr J. Interleukin 1 and tumor necrosis factor stimulate human vascular endothelial cells to promote transendothelial neutrophil passage. J Clin Invest. 1989 Feb;83(2):444–455. doi: 10.1172/JCI113903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Patarroyo M., Clark E. A., Prieto J., Kantor C., Gahmberg C. G. Identification of a novel adhesion molecule in human leukocytes by monoclonal antibody LB-2. FEBS Lett. 1987 Jan 5;210(2):127–131. doi: 10.1016/0014-5793(87)81321-2. [DOI] [PubMed] [Google Scholar]
  25. Phillips M. L., Nudelman E., Gaeta F. C., Perez M., Singhal A. K., Hakomori S., Paulson J. C. ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. Science. 1990 Nov 23;250(4984):1130–1132. doi: 10.1126/science.1701274. [DOI] [PubMed] [Google Scholar]
  26. Pober J. S., Gimbrone M. A., Jr, Lapierre L. A., Mendrick D. L., Fiers W., Rothlein R., Springer T. A. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986 Sep 15;137(6):1893–1896. [PubMed] [Google Scholar]
  27. Pohlman T. H., Stanness K. A., Beatty P. G., Ochs H. D., Harlan J. M. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, and tumor necrosis factor-alpha increases neutrophil adherence by a CDw18-dependent mechanism. J Immunol. 1986 Jun 15;136(12):4548–4553. [PubMed] [Google Scholar]
  28. Prescott S. M., Zimmerman G. A., McIntyre T. M. Human endothelial cells in culture produce platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when stimulated with thrombin. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3534–3538. doi: 10.1073/pnas.81.11.3534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rosen H., Gordon S. Monoclonal antibody to the murine type 3 complement receptor inhibits adhesion of myelomonocytic cells in vitro and inflammatory cell recruitment in vivo. J Exp Med. 1987 Dec 1;166(6):1685–1701. doi: 10.1084/jem.166.6.1685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schleimer R. P., Rutledge B. K. Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin, and tumor-promoting phorbol diesters. J Immunol. 1986 Jan;136(2):649–654. [PubMed] [Google Scholar]
  31. Smith C. W., Rothlein R., Hughes B. J., Mariscalco M. M., Rudloff H. E., Schmalstieg F. C., Anderson D. C. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest. 1988 Nov;82(5):1746–1756. doi: 10.1172/JCI113788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  33. Tuomanen E. I., Saukkonen K., Sande S., Cioffe C., Wright S. D. Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med. 1989 Sep 1;170(3):959–969. doi: 10.1084/jem.170.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vedder N. B., Harlan J. M. Increased surface expression of CD11b/CD18 (Mac-1) is not required for stimulated neutrophil adherence to cultured endothelium. J Clin Invest. 1988 Mar;81(3):676–682. doi: 10.1172/JCI113372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Walz G., Aruffo A., Kolanus W., Bevilacqua M., Seed B. Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells. Science. 1990 Nov 23;250(4984):1132–1135. doi: 10.1126/science.1701275. [DOI] [PubMed] [Google Scholar]
  36. Wheeler M. E., Luscinskas F. W., Bevilacqua M. P., Gimbrone M. A., Jr Cultured human endothelial cells stimulated with cytokines or endotoxin produce an inhibitor of leukocyte adhesion. J Clin Invest. 1988 Oct;82(4):1211–1218. doi: 10.1172/JCI113718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wright S. D., Detmers P. A. Adhesion-promoting receptors on phagocytes. J Cell Sci Suppl. 1988;9:99–120. doi: 10.1242/jcs.1988.supplement_9.5. [DOI] [PubMed] [Google Scholar]
  38. Wright S. D., Jong M. T. Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide. J Exp Med. 1986 Dec 1;164(6):1876–1888. doi: 10.1084/jem.164.6.1876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wright S. D., Levin S. M., Jong M. T., Chad Z., Kabbash L. G. CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide. J Exp Med. 1989 Jan 1;169(1):175–183. doi: 10.1084/jem.169.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wright S. D., Meyer B. C. Phorbol esters cause sequential activation and deactivation of complement receptors on polymorphonuclear leukocytes. J Immunol. 1986 Mar 1;136(5):1759–1764. [PubMed] [Google Scholar]
  41. Wright S. D., Rao P. E., Van Voorhis W. C., Craigmyle L. S., Iida K., Talle M. A., Westberg E. F., Goldstein G., Silverstein S. C. Identification of the C3bi receptor of human monocytes and macrophages by using monoclonal antibodies. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5699–5703. doi: 10.1073/pnas.80.18.5699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wright S. D., Silverstein S. C. Tumor-promoting phorbol esters stimulate C3b and C3b' receptor-mediated phagocytosis in cultured human monocytes. J Exp Med. 1982 Oct 1;156(4):1149–1164. doi: 10.1084/jem.156.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wright S. D., Tobias P. S., Ulevitch R. J., Ramos R. A. Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages. J Exp Med. 1989 Oct 1;170(4):1231–1241. doi: 10.1084/jem.170.4.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wright S. D., Weitz J. I., Huang A. J., Levin S. M., Silverstein S. C., Loike J. D. Complement receptor type three (CD11b/CD18) of human polymorphonuclear leukocytes recognizes fibrinogen. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7734–7738. doi: 10.1073/pnas.85.20.7734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zimmerman G. A., McIntyre T. M., Mehra M., Prescott S. M. Endothelial cell-associated platelet-activating factor: a novel mechanism for signaling intercellular adhesion. J Cell Biol. 1990 Feb;110(2):529–540. doi: 10.1083/jcb.110.2.529. [DOI] [PMC free article] [PubMed] [Google Scholar]

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