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. 1995 May;63(5):1835–1839. doi: 10.1128/iai.63.5.1835-1839.1995

Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression.

L Yao 1, V Bengualid 1, F D Lowy 1, J J Gibbons 1, V B Hatcher 1, J W Berman 1
PMCID: PMC173232  PMID: 7729892

Abstract

The ability of the vascular endothelium to elaborate cytokines in response to gram-positive sepsis has received limited attention. This study examined cytokine expression by human umbilical vein endothelial cells (EC) following infection with a gram-positive bacterial pathogen, Staphylococcus aureus. S. aureus infection of EC resulted in the production of interleukin-6 (IL-6) and IL-1 beta. For IL-6, message was detected at 3 h after infection, protein was present at 24 h, and both message and protein persisted for 72 h. IL-1 beta message was detected at 12 h, IL-1 beta protein was detected at 24 h, and both persisted for 72 h. Message for colony-stimulating factor 1 remained unaltered. UV-killed S. aureus also elicited IL-1 beta and IL-6 message and protein expression at 24 and 48 h. Twenty-one clinical isolates of S. aureus were tested, and all induced IL-6 release by 48 h. However, the laboratory strain 8325-4 did not induce cytokine expression at any time point and was internalized by EC 1,000-fold less than other strains were. Internalization of latex beads by EC did not induce IL-6 gene expression. Furthermore, cytochalasin D treatment of the EC prevented IL-1 and IL-6 induction by S. aureus but not by tumor necrosis factor alpha or lipopolysaccharide. These results indicate that S. aureus is a potent inducer of IL-1 and IL-6 in EC and that internalization of S. aureus by EC is necessary for their cytokine expression. Thus, our data suggest that the vascular endothelium may play an important role in the pathogenesis of septicemia caused by gram-positive organisms.

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Selected References

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  1. Akira S., Hirano T., Taga T., Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990 Aug;4(11):2860–2867. [PubMed] [Google Scholar]
  2. Beilke M. A. Vascular endothelium in immunology and infectious disease. Rev Infect Dis. 1989 Mar-Apr;11(2):273–283. doi: 10.1093/clinids/11.2.273. [DOI] [PubMed] [Google Scholar]
  3. Bengualid V., Hatcher V. B., Diamond B., Blumberg E. A., Lowy F. D. Staphylococcus aureus infection of human endothelial cells potentiates Fc receptor expression. J Immunol. 1990 Dec 15;145(12):4279–4283. [PubMed] [Google Scholar]
  4. Bhakdi S., Klonisch T., Nuber P., Fischer W. Stimulation of monokine production by lipoteichoic acids. Infect Immun. 1991 Dec;59(12):4614–4620. doi: 10.1128/iai.59.12.4614-4620.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  6. Calandra T., Baumgartner J. D., Grau G. E., Wu M. M., Lambert P. H., Schellekens J., Verhoef J., Glauser M. P. Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group. J Infect Dis. 1990 May;161(5):982–987. doi: 10.1093/infdis/161.5.982. [DOI] [PubMed] [Google Scholar]
  7. Calandra T., Gerain J., Heumann D., Baumgartner J. D., Glauser M. P. High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group. Am J Med. 1991 Jul;91(1):23–29. doi: 10.1016/0002-9343(91)90069-a. [DOI] [PubMed] [Google Scholar]
  8. Casey L. C., Balk R. A., Bone R. C. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med. 1993 Oct 15;119(8):771–778. doi: 10.7326/0003-4819-119-8-199310150-00001. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Conn G., Hatcher V. B. The isolation and purification of two anionic endothelial cell growth factors from human brain. Biochem Biophys Res Commun. 1984 Oct 15;124(1):262–268. doi: 10.1016/0006-291x(84)90946-x. [DOI] [PubMed] [Google Scholar]
  11. Dinarello C. A., Gelfand J. A., Wolff S. M. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. JAMA. 1993 Apr 14;269(14):1829–1835. [PubMed] [Google Scholar]
  12. Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
  13. Gordon P. B., Sussman I. I., Hatcher V. B. Long-term culture of human endothelial cells. In Vitro. 1983 Sep;19(9):661–671. doi: 10.1007/BF02628957. [DOI] [PubMed] [Google Scholar]
  14. Hamill R. J., Vann J. M., Proctor R. A. Phagocytosis of Staphylococcus aureus by cultured bovine aortic endothelial cells: model for postadherence events in endovascular infections. Infect Immun. 1986 Dec;54(3):833–836. doi: 10.1128/iai.54.3.833-836.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hazuda D. J., Lee J. C., Young P. R. The kinetics of interleukin 1 secretion from activated monocytes. Differences between interleukin 1 alpha and interleukin 1 beta. J Biol Chem. 1988 Jun 15;263(17):8473–8479. [PubMed] [Google Scholar]
  16. Hesse D. G., Tracey K. J., Fong Y., Manogue K. R., Palladino M. A., Jr, Cerami A., Shires G. T., Lowry S. F. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet. 1988 Feb;166(2):147–153. [PubMed] [Google Scholar]
  17. Keller R., Fischer W., Keist R., Bassetti S. Macrophage response to bacteria: induction of marked secretory and cellular activities by lipoteichoic acids. Infect Immun. 1992 Sep;60(9):3664–3672. doi: 10.1128/iai.60.9.3664-3672.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lewis S. A., Lee M. G., Cowan N. J. Five mouse tubulin isotypes and their regulated expression during development. J Cell Biol. 1985 Sep;101(3):852–861. doi: 10.1083/jcb.101.3.852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lowy F. D., Fant J., Higgins L. L., Ogawa S. K., Hatcher V. B. Staphylococcus aureus--human endothelial cell interactions. J Ultrastruct Mol Struct Res. 1988 Feb;98(2):137–146. doi: 10.1016/s0889-1605(88)80906-6. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Miossec P., Cavender D., Ziff M. Production of interleukin 1 by human endothelial cells. J Immunol. 1986 Apr 1;136(7):2486–2491. [PubMed] [Google Scholar]
  22. Novick R. P. Genetic systems in staphylococci. Methods Enzymol. 1991;204:587–636. doi: 10.1016/0076-6879(91)04029-n. [DOI] [PubMed] [Google Scholar]
  23. Ogawa S. K., Yurberg E. R., Hatcher V. B., Levitt M. A., Lowy F. D. Bacterial adherence to human endothelial cells in vitro. Infect Immun. 1985 Oct;50(1):218–224. doi: 10.1128/iai.50.1.218-224.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ohlsson K., Björk P., Bergenfeldt M., Hageman R., Thompson R. C. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990 Dec 6;348(6301):550–552. doi: 10.1038/348550a0. [DOI] [PubMed] [Google Scholar]
  25. Parrillo J. E. Pathogenetic mechanisms of septic shock. N Engl J Med. 1993 May 20;328(20):1471–1477. doi: 10.1056/NEJM199305203282008. [DOI] [PubMed] [Google Scholar]
  26. Phonimdaeng P., O'Reilly M., O'Toole P. W., Foster T. J. Molecular cloning and expression of the coagulase gene of Staphylococcus aureus 8325-4. J Gen Microbiol. 1988 Jan;134(1):75–83. doi: 10.1099/00221287-134-1-75. [DOI] [PubMed] [Google Scholar]
  27. Pober J. S., Cotran R. S. The role of endothelial cells in inflammation. Transplantation. 1990 Oct;50(4):537–544. doi: 10.1097/00007890-199010000-00001. [DOI] [PubMed] [Google Scholar]
  28. Read M. A., Cordle S. R., Veach R. A., Carlisle C. D., Hawiger J. Cell-free pool of CD14 mediates activation of transcription factor NF-kappa B by lipopolysaccharide in human endothelial cells. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9887–9891. doi: 10.1073/pnas.90.21.9887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. See R. H., Chow A. W. Staphylococcal toxic shock syndrome toxin 1-induced tumor necrosis factor alpha and interleukin-1 beta secretion by human peripheral blood monocytes and T lymphocytes is differentially suppressed by protein kinase inhibitors. Infect Immun. 1992 Aug;60(8):3456–3459. doi: 10.1128/iai.60.8.3456-3459.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Standiford T. J., Arenberg D. A., Danforth J. M., Kunkel S. L., VanOtteren G. M., Strieter R. M. Lipoteichoic acid induces secretion of interleukin-8 from human blood monocytes: a cellular and molecular analysis. Infect Immun. 1994 Jan;62(1):119–125. doi: 10.1128/iai.62.1.119-125.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Timmerman C. P., Mattsson E., Martinez-Martinez L., De Graaf L., Van Strijp J. A., Verbrugh H. A., Verhoef J., Fleer A. Induction of release of tumor necrosis factor from human monocytes by staphylococci and staphylococcal peptidoglycans. Infect Immun. 1993 Oct;61(10):4167–4172. doi: 10.1128/iai.61.10.4167-4172.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tompkins D. C., Hatcher V. B., Patel D., Orr G. A., Higgins L. L., Lowy F. D. A human endothelial cell membrane protein that binds Staphylococcus aureus in vitro. J Clin Invest. 1990 Apr;85(4):1248–1254. doi: 10.1172/JCI114560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  34. Tracey K. J., Lowry S. F. The role of cytokine mediators in septic shock. Adv Surg. 1990;23:21–56. [PubMed] [Google Scholar]
  35. Vann J. M., Proctor R. A. Ingestion of Staphylococcus aureus by bovine endothelial cells results in time- and inoculum-dependent damage to endothelial cell monolayers. Infect Immun. 1987 Sep;55(9):2155–2163. doi: 10.1128/iai.55.9.2155-2163.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  37. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [PubMed] [Google Scholar]

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