Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Dec 1;174(6):1517–1526. doi: 10.1084/jem.174.6.1517

Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites

PMCID: PMC2119026  PMID: 1744583

Abstract

Lipopolysaccharide (LPS) activation of cells of monocytic lineage leads to rapid and transient expression of a set of inflammatory gene products, including tissue factor (TF). This transmembrane receptor is the major cellular initiator of the blood coagulation cascades, and induced expression of TF is postulated to play a role in inflammation. Functional studies using transfected THP-1 monocytic cells revealed the presence of a 56-bp LPS response element (LRE) within the TF promoter that conferred LPS responsiveness to a heterologous promoter. LPS stimulation of these cells activated proteins that bound to nucleotide sequences within the LRE resembling consensus binding sites for activator protein 1 (AP-1) and nuclear factor kappa B (NF-kappa B). Induction of the TF gene may represent a prototypic example of gene activation in monocytic cells by assembly of transcription factor complexes, and may clarify the role of AP-1 and NF-kappa B in the regulation of other LPS-responsive genes.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Akira S., Isshiki H., Sugita T., Tanabe O., Kinoshita S., Nishio Y., Nakajima T., Hirano T., Kishimoto T. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990 Jun;9(6):1897–1906. doi: 10.1002/j.1460-2075.1990.tb08316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Auwerx J., Sassone-Corsi P. IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. Cell. 1991 Mar 8;64(5):983–993. doi: 10.1016/0092-8674(91)90322-p. [DOI] [PubMed] [Google Scholar]
  3. Bach R. R. Initiation of coagulation by tissue factor. CRC Crit Rev Biochem. 1988;23(4):339–368. doi: 10.3109/10409238809082548. [DOI] [PubMed] [Google Scholar]
  4. Bauer J., Ganter U., Geiger T., Jacobshagen U., Hirano T., Matsuda T., Kishimoto T., Andus T., Acs G., Gerok W. Regulation of interleukin-6 expression in cultured human blood monocytes and monocyte-derived macrophages. Blood. 1988 Oct;72(4):1134–1140. [PubMed] [Google Scholar]
  5. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  6. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  7. Brand K., Fowler B. J., Edgington T. S., Mackman N. Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. Mol Cell Biol. 1991 Sep;11(9):4732–4738. doi: 10.1128/mcb.11.9.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brasier A. R., Ron D., Tate J. E., Habener J. F. A family of constitutive C/EBP-like DNA binding proteins attenuate the IL-1 alpha induced, NF kappa B mediated trans-activation of the angiotensinogen gene acute-phase response element. EMBO J. 1990 Dec;9(12):3933–3944. doi: 10.1002/j.1460-2075.1990.tb07614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  10. Collart M. A., Baeuerle P., Vassalli P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol. 1990 Apr;10(4):1498–1506. doi: 10.1128/mcb.10.4.1498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Curran T., Franza B. R., Jr Fos and Jun: the AP-1 connection. Cell. 1988 Nov 4;55(3):395–397. doi: 10.1016/0092-8674(88)90024-4. [DOI] [PubMed] [Google Scholar]
  12. Edwards R. L., Rickles F. R. Macrophage procoagulants. Prog Hemost Thromb. 1984;7:183–209. [PubMed] [Google Scholar]
  13. Fan S. T., Edgington T. S. Clonal analysis of mechanisms of murine T helper cell collaboration with effector cells of macrophage lineage. J Immunol. 1988 Sep 15;141(6):1819–1827. [PubMed] [Google Scholar]
  14. Fujita T., Shibuya H., Ohashi T., Yamanishi K., Taniguchi T. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes. Cell. 1986 Aug 1;46(3):401–405. doi: 10.1016/0092-8674(86)90660-4. [DOI] [PubMed] [Google Scholar]
  15. Geczy C. L., Farram E., Moon D. K., Meyer P. A., McKenzie I. F. Macrophage procoagulant activity as a measure of cell-mediated immunity in the mouse. J Immunol. 1983 Jun;130(6):2743–2749. [PubMed] [Google Scholar]
  16. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  17. Ghosh S., Gifford A. M., Riviere L. R., Tempst P., Nolan G. P., Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019–1029. doi: 10.1016/0092-8674(90)90276-k. [DOI] [PubMed] [Google Scholar]
  18. Goldfeld A. E., Doyle C., Maniatis T. Human tumor necrosis factor alpha gene regulation by virus and lipopolysaccharide. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9769–9773. doi: 10.1073/pnas.87.24.9769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gregory S. A., Edgington T. S. Tissue factor induction in human monocytes. Two distinct mechanisms displayed by different alloantigen-responsive T cell clones. J Clin Invest. 1985 Dec;76(6):2440–2445. doi: 10.1172/JCI112260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gregory S. A., Kornbluth R. S., Helin H., Remold H. G., Edgington T. S. Monocyte procoagulant inducing factor: a lymphokine involved in the T cell-instructed monocyte procoagulant response to antigen. J Immunol. 1986 Nov 15;137(10):3231–3239. [PubMed] [Google Scholar]
  22. Gregory S. A., Morrissey J. H., Edgington T. S. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol. 1989 Jun;9(6):2752–2755. doi: 10.1128/mcb.9.6.2752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Haas J. G., Baeuerle P. A., Riethmüller G., Ziegler-Heitbrock H. W. Molecular mechanisms in down-regulation of tumor necrosis factor expression. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9563–9567. doi: 10.1073/pnas.87.24.9563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Helin H., Edgington T. S. Allogeneic induction of the human T cell-instructed monocyte procoagulant response is rapid and is elicited by HLA-DR. J Exp Med. 1983 Sep 1;158(3):962–975. doi: 10.1084/jem.158.3.962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Isshiki H., Akira S., Tanabe O., Nakajima T., Shimamoto T., Hirano T., Kishimoto T. Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. Mol Cell Biol. 1990 Jun;10(6):2757–2764. doi: 10.1128/mcb.10.6.2757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kieran M., Blank V., Logeat F., Vandekerckhove J., Lottspeich F., Le Bail O., Urban M. B., Kourilsky P., Baeuerle P. A., Israël A. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007–1018. doi: 10.1016/0092-8674(90)90275-j. [DOI] [PubMed] [Google Scholar]
  28. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  29. Libermann T. A., Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990 May;10(5):2327–2334. doi: 10.1128/mcb.10.5.2327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mackman N., Fowler B. J., Edgington T. S., Morrissey J. H. Functional analysis of the human tissue factor promoter and induction by serum. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2254–2258. doi: 10.1073/pnas.87.6.2254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mackman N., Morrissey J. H., Fowler B., Edgington T. S. Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade. Biochemistry. 1989 Feb 21;28(4):1755–1762. doi: 10.1021/bi00430a050. [DOI] [PubMed] [Google Scholar]
  32. Mauxion F., Jamieson C., Yoshida M., Arai K., Sen R. Comparison of constitutive and inducible transcriptional enhancement mediated by kappa B-related sequences: modulation of activity in B cells by human T-cell leukemia virus type I tax gene. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2141–2145. doi: 10.1073/pnas.88.6.2141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Molitor J. A., Walker W. H., Doerre S., Ballard D. W., Greene W. C. NF-kappa B: a family of inducible and differentially expressed enhancer-binding proteins in human T cells. Proc Natl Acad Sci U S A. 1990 Dec;87(24):10028–10032. doi: 10.1073/pnas.87.24.10028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Muegge K., Williams T. M., Kant J., Karin M., Chiu R., Schmidt A., Siebenlist U., Young H. A., Durum S. K. Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1. Science. 1989 Oct 13;246(4927):249–251. doi: 10.1126/science.2799385. [DOI] [PubMed] [Google Scholar]
  35. Mukaida N., Mahe Y., Matsushima K. Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem. 1990 Dec 5;265(34):21128–21133. [PubMed] [Google Scholar]
  36. Niemetz J., Fani K. Role of leukocytes in blood coagulation and the generalized Shwartzman reaction. Nat New Biol. 1971 Aug 25;232(34):247–248. doi: 10.1038/newbio232247a0. [DOI] [PubMed] [Google Scholar]
  37. Pomerantz R. J., Feinberg M. B., Trono D., Baltimore D. Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression. J Exp Med. 1990 Jul 1;172(1):253–261. doi: 10.1084/jem.172.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ray A., Sassone-Corsi P., Sehgal P. B. A multiple cytokine- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. Mol Cell Biol. 1989 Dec;9(12):5537–5547. doi: 10.1128/mcb.9.12.5537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ruf W., Rehemtulla A., Morrissey J. H., Edgington T. S. Phospholipid-independent and -dependent interactions required for tissue factor receptor and cofactor function. J Biol Chem. 1991 Feb 5;266(4):2158–2166. [PubMed] [Google Scholar]
  40. Schumann R. R., Leong S. R., Flaggs G. W., Gray P. W., Wright S. D., Mathison J. C., Tobias P. S., Ulevitch R. J. Structure and function of lipopolysaccharide binding protein. Science. 1990 Sep 21;249(4975):1429–1431. doi: 10.1126/science.2402637. [DOI] [PubMed] [Google Scholar]
  41. Shakhov A. N., Collart M. A., Vassalli P., Nedospasov S. A., Jongeneel C. V. Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med. 1990 Jan 1;171(1):35–47. doi: 10.1084/jem.171.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shimizu H., Mitomo K., Watanabe T., Okamoto S., Yamamoto K. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol. 1990 Feb;10(2):561–568. doi: 10.1128/mcb.10.2.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Singh H., Sen R., Baltimore D., Sharp P. A. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature. 1986 Jan 9;319(6049):154–158. doi: 10.1038/319154a0. [DOI] [PubMed] [Google Scholar]
  44. Taylor F. B., Jr, Chang A., Ruf W., Morrissey J. H., Hinshaw L., Catlett R., Blick K., Edgington T. S. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock. 1991 Mar;33(3):127–134. [PubMed] [Google Scholar]
  45. 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]
  46. Vu T. K., Hung D. T., Wheaton V. I., Coughlin S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991 Mar 22;64(6):1057–1068. doi: 10.1016/0092-8674(91)90261-v. [DOI] [PubMed] [Google Scholar]
  47. Wright S. D., Ramos R. A., Tobias P. S., Ulevitch R. J., Mathison J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]
  48. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. van Zonneveld A. J., Curriden S. A., Loskutoff D. J. Type 1 plasminogen activator inhibitor gene: functional analysis and glucocorticoid regulation of its promoter. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5525–5529. doi: 10.1073/pnas.85.15.5525. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES