Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Nov;65(11):4822–4831. doi: 10.1128/iai.65.11.4822-4831.1997

Role of tumor necrosis factor alpha in induction of murine CD14 gene expression by lipopolysaccharide.

C Fearns 1, D J Loskutoff 1
PMCID: PMC175692  PMID: 9353071

Abstract

We previously demonstrated CD14 gene expression in myeloid and epithelial cells of the mouse and showed that expression of the CD14 gene in both is modulated by lipopolysaccharide (LPS). Here we test the hypothesis that the induction of CD14 in these cells is an indirect effect of LPS, one mediated by tumor necrosis factor alpha (TNF-alpha). TNF-alpha induced a transient increase in levels of CD14 in plasma with a peak at 6 to 8 h, and this increase in levels of CD14 antigen in plasma was accompanied by increased levels of CD14 mRNA in lung, liver, and kidney. Moreover, in situ hybridization studies revealed that CD14 mRNA was induced in both myeloid cells and epithelial cells, the same cells that respond to LPS. Pretreatment of mice with anti-TNF antiserum reduced the LPS-mediated increase in levels of CD14 in plasma and significantly reduced the level of induction of CD14 mRNA in selected epithelial cells in the kidney and liver. The antiserum did not appear to block LPS-mediated induction in myeloid cells in the tissues examined. In C3H/HeJ mice, the epithelial response to LPS was markedly attenuated whereas the response to TNF-alpha was normal. Thus, regulation of CD14 gene expression by LPS differs in epithelial and myeloid cells, with the epithelial responses in kidney and liver being mediated, in part, by TNF-alpha.

Full Text

The Full Text of this article is available as a PDF (2.6 MB).

Selected References

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

  1. Aderka D., Engelmann H., Maor Y., Brakebusch C., Wallach D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med. 1992 Feb 1;175(2):323–329. doi: 10.1084/jem.175.2.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ashkenazi A., Marsters S. A., Capon D. J., Chamow S. M., Figari I. S., Pennica D., Goeddel D. V., Palladino M. A., Smith D. H. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10535–10539. doi: 10.1073/pnas.88.23.10535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bauss F., Dröge W., Männel D. N. Tumor necrosis factor mediates endotoxic effects in mice. Infect Immun. 1987 Jul;55(7):1622–1625. doi: 10.1128/iai.55.7.1622-1625.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Butler L. D., Layman N. K., Cain R. L., Riedl P. E., Mohler K. M., Bobbitt J. L., Belagajie R., Sharp J., Bendele A. M. Interleukin 1-induced pathophysiology: induction of cytokines, development of histopathologic changes, and immunopharmacologic intervention. Clin Immunol Immunopathol. 1989 Dec;53(3):400–421. doi: 10.1016/0090-1229(89)90003-2. [DOI] [PubMed] [Google Scholar]
  6. Chensue S. W., Terebuh P. D., Remick D. G., Scales W. E., Kunkel S. L. In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. Am J Pathol. 1991 Feb;138(2):395–402. [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Endo S., Inada K., Kasai T., Takakuwa T., Nakae H., Kikuchi M., Yamashita H., Yoshida M. Soluble CD14 (sCD14) levels in patients with multiple organ failure (MOF). Res Commun Chem Pathol Pharmacol. 1994 Apr;84(1):17–25. [PubMed] [Google Scholar]
  9. Fearns C., Kravchenko V. V., Ulevitch R. J., Loskutoff D. J. Murine CD14 gene expression in vivo: extramyeloid synthesis and regulation by lipopolysaccharide. J Exp Med. 1995 Mar 1;181(3):857–866. doi: 10.1084/jem.181.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fong Y. M., Marano M. A., Moldawer L. L., Wei H., Calvano S. E., Kenney J. S., Allison A. C., Cerami A., Shires G. T., Lowry S. F. The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest. 1990 Jun;85(6):1896–1904. doi: 10.1172/JCI114651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fong Y., Tracey K. J., Moldawer L. L., Hesse D. G., Manogue K. B., Kenney J. S., Lee A. T., Kuo G. C., Allison A. C., Lowry S. F. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med. 1989 Nov 1;170(5):1627–1633. doi: 10.1084/jem.170.5.1627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Frey E. A., Miller D. S., Jahr T. G., Sundan A., Bazil V., Espevik T., Finlay B. B., Wright S. D. Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med. 1992 Dec 1;176(6):1665–1671. doi: 10.1084/jem.176.6.1665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giroir B. P., Johnson J. H., Brown T., Allen G. L., Beutler B. The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia. J Clin Invest. 1992 Sep;90(3):693–698. doi: 10.1172/JCI115939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Golenbock D. T., Bach R. R., Lichenstein H., Juan T. S., Tadavarthy A., Moldow C. F. Soluble CD14 promotes LPS activation of CD14-deficient PNH monocytes and endothelial cells. J Lab Clin Med. 1995 May;125(5):662–671. [PubMed] [Google Scholar]
  15. Grunwald U., Krüger C., Schütt C. Endotoxin-neutralizing capacity of soluble CD14 is a highly conserved specific function. Circ Shock. 1993 Mar;39(3):220–225. [PubMed] [Google Scholar]
  16. Hailman E., Lichenstein H. S., Wurfel M. M., Miller D. S., Johnson D. A., Kelley M., Busse L. A., Zukowski M. M., Wright S. D. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med. 1994 Jan 1;179(1):269–277. doi: 10.1084/jem.179.1.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hailman E., Vasselon T., Kelley M., Busse L. A., Hu M. C., Lichenstein H. S., Detmers P. A., Wright S. D. Stimulation of macrophages and neutrophils by complexes of lipopolysaccharide and soluble CD14. J Immunol. 1996 Jun 1;156(11):4384–4390. [PubMed] [Google Scholar]
  18. Haziot A., Rong G. W., Bazil V., Silver J., Goyert S. M. Recombinant soluble CD14 inhibits LPS-induced tumor necrosis factor-alpha production by cells in whole blood. J Immunol. 1994 Jun 15;152(12):5868–5876. [PubMed] [Google Scholar]
  19. Haziot A., Rong G. W., Lin X. Y., Silver J., Goyert S. M. Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol. 1995 Jun 15;154(12):6529–6532. [PubMed] [Google Scholar]
  20. Haziot A., Rong G. W., Silver J., Goyert S. M. Recombinant soluble CD14 mediates the activation of endothelial cells by lipopolysaccharide. J Immunol. 1993 Aug 1;151(3):1500–1507. [PubMed] [Google Scholar]
  21. Hoffmann R., Grewe M., Estler H. C., Schulze-Specking A., Decker K. Regulation of tumor necrosis factor-alpha-mRNA synthesis and distribution of tumor necrosis factor-alpha-mRNA synthesizing cells in rat liver during experimental endotoxemia. J Hepatol. 1994 Jan;20(1):122–128. doi: 10.1016/s0168-8278(05)80478-7. [DOI] [PubMed] [Google Scholar]
  22. Hunt J. S., Chen H. L., Hu X. L., Chen T. Y., Morrison D. C. Tumor necrosis factor-alpha gene expression in the tissues of normal mice. Cytokine. 1992 Sep;4(5):340–346. doi: 10.1016/1043-4666(92)90076-4. [DOI] [PubMed] [Google Scholar]
  23. Ikewaki N., Inoko H. Induction of CD14 antigen on the surface of U937 cells by an interleukin-6 autocrine mechanism after culture with formalin-killed gram-negative bacteria. Tissue Antigens. 1991 Sep;38(3):117–123. doi: 10.1111/j.1399-0039.1991.tb02024.x. [DOI] [PubMed] [Google Scholar]
  24. Jevnikar A. M., Wuthrich R. P., Brennan D. C., Maslinski W., Glimcher L. H., Rubin-Kelley V. E. TNF-alpha is expressed on the surface of kidney proximal tubular cells. Transplant Proc. 1991 Feb;23(1 Pt 1):231–232. [PubMed] [Google Scholar]
  25. Labeta M. O., Durieux J. J., Fernandez N., Herrmann R., Ferrara P. Release from a human monocyte-like cell line of two different soluble forms of the lipopolysaccharide receptor, CD14. Eur J Immunol. 1993 Sep;23(9):2144–2151. doi: 10.1002/eji.1830230915. [DOI] [PubMed] [Google Scholar]
  26. Labeta M. O., Durieux J. J., Spagnoli G., Fernandez N., Wijdenes J., Herrmann R. CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis. Immunology. 1993 Nov;80(3):415–423. [PMC free article] [PubMed] [Google Scholar]
  27. Le J., Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987 Mar;56(3):234–248. [PubMed] [Google Scholar]
  28. Lorenz H. M., Antoni C., Valerius T., Repp R., Grünke M., Schwerdtner N., Nüsslein H., Woody J., Kalden J. R., Manger B. In vivo blockade of TNF-alpha by intravenous infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J Immunol. 1996 Feb 15;156(4):1646–1653. [PubMed] [Google Scholar]
  29. Luster M. I., Germolec D. R., Yoshida T., Kayama F., Thompson M. Endotoxin-induced cytokine gene expression and excretion in the liver. Hepatology. 1994 Feb;19(2):480–488. [PubMed] [Google Scholar]
  30. Matsuura K., Ishida T., Setoguchi M., Higuchi Y., Akizuki S., Yamamoto S. Upregulation of mouse CD14 expression in Kupffer cells by lipopolysaccharide. J Exp Med. 1994 May 1;179(5):1671–1676. doi: 10.1084/jem.179.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Morrison D. C., Ulevitch R. J. The effects of bacterial endotoxins on host mediation systems. A review. Am J Pathol. 1978 Nov;93(2):526–618. [PMC free article] [PubMed] [Google Scholar]
  32. Neumann B., Machleidt T., Lifka A., Pfeffer K., Vestweber D., Mak T. W., Holzmann B., Krönke M. Crucial role of 55-kilodalton TNF receptor in TNF-induced adhesion molecule expression and leukocyte organ infiltration. J Immunol. 1996 Feb 15;156(4):1587–1593. [PubMed] [Google Scholar]
  33. Pugin J., Schürer-Maly C. C., Leturcq D., Moriarty A., Ulevitch R. J., Tobias P. S. Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2744–2748. doi: 10.1073/pnas.90.7.2744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Schumann R. R. Function of lipopolysaccharide (LPS)-binding protein (LBP) and CD14, the receptor for LPS/LBP complexes: a short review. Res Immunol. 1992 Jan;143(1):11–15. doi: 10.1016/0923-2494(92)80074-u. [DOI] [PubMed] [Google Scholar]
  36. Schütt C., Schilling T., Grunwald U., Schönfeld W., Krüger C. Endotoxin-neutralizing capacity of soluble CD14. Res Immunol. 1992 Jan;143(1):71–78. doi: 10.1016/0923-2494(92)80082-v. [DOI] [PubMed] [Google Scholar]
  37. Takakuwa T., Knopf H. P., Sing A., Carsetti R., Galanos C., Freudenberg M. A. Induction of CD14 expression in Lpsn, Lpsd and tumor necrosis factor receptor-deficient mice. Eur J Immunol. 1996 Nov;26(11):2686–2692. doi: 10.1002/eji.1830261121. [DOI] [PubMed] [Google Scholar]
  38. Van Zee K. J., Kohno T., Fischer E., Rock C. S., Moldawer L. L., Lowry S. F. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845–4849. doi: 10.1073/pnas.89.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Weingarten R., Sklar L. A., Mathison J. C., Omidi S., Ainsworth T., Simon S., Ulevitch R. J., Tobias P. S. Interactions of lipopolysaccharide with neutrophils in blood via CD14. J Leukoc Biol. 1993 May;53(5):518–524. doi: 10.1002/jlb.53.5.518. [DOI] [PubMed] [Google Scholar]
  40. Wright S. D., Ramos R. A., Hermanowski-Vosatka A., Rockwell P., Detmers P. A. Activation of the adhesive capacity of CR3 on neutrophils by endotoxin: dependence on lipopolysaccharide binding protein and CD14. J Exp Med. 1991 May 1;173(5):1281–1286. doi: 10.1084/jem.173.5.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. Zanetti G., Heumann D., Gérain J., Kohler J., Abbet P., Barras C., Lucas R., Glauser M. P., Baumgartner J. D. Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-alpha and to lipopolysaccharide. J Immunol. 1992 Mar 15;148(6):1890–1897. [PubMed] [Google Scholar]
  43. Ziegler-Heitbrock H. W., Ulevitch R. J. CD14: cell surface receptor and differentiation marker. Immunol Today. 1993 Mar;14(3):121–125. doi: 10.1016/0167-5699(93)90212-4. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES