Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1998 Feb 15;330(Pt 1):67–72. doi: 10.1042/bj3300067

Annexins I and II bind to lipid A: a possible role in the inhibition of endotoxins.

D A Eberhard 1, S R Vandenberg 1
PMCID: PMC1219109  PMID: 9461492

Abstract

Annexins are Ca2+-dependent phospholipid-binding proteins with anti-inflammatory properties that are present on the surfaces of, and released from, certain cell types, such as leukocytes and secretory epithelia. The present study investigated the possibility that annexins may bind directly to bacterial endotoxin, inhibiting its interactions with cellular receptors or accessory binding proteins. An enzyme-linked immunoassay demonstrated calcium-dependent binding of low nanomolar concentrations of annexin-I and annexin-II p36/p11 heterotetramer to lipid A. In contrast, little or no annexin binding to lipopolysaccharide (LPS) was detected under similar conditions. LPS-binding protein binding to lipid A was blocked by annexin-I, and the annexins inhibited nitrite generation in RAW 264.7 cells induced by lipid A but not that induced by LPS. The data suggest that direct binding of annexins to lipid A may represent a mechanism for suppressing cellular and systemic responses to endotoxin.

Full Text

The Full Text of this article is available as a PDF (415.0 KB).

Selected References

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

  1. Christmas P., Callaway J., Fallon J., Jones J., Haigler H. T. Selective secretion of annexin 1, a protein without a signal sequence, by the human prostate gland. J Biol Chem. 1991 Feb 5;266(4):2499–2507. [PubMed] [Google Scholar]
  2. Chung C. Y., Erickson H. P. Cell surface annexin II is a high affinity receptor for the alternatively spliced segment of tenascin-C. J Cell Biol. 1994 Jul;126(2):539–548. doi: 10.1083/jcb.126.2.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Croxtal J. D., Newman S. P., Choudhury Q., Flower R. J. The concerted regulation of cPLA2, COX2, and lipocortin 1 expression by IL-1beta in A549 cells. Biochem Biophys Res Commun. 1996 Mar 27;220(3):491–495. doi: 10.1006/bbrc.1996.0432. [DOI] [PubMed] [Google Scholar]
  4. Davis R. G., Vishwanatha J. K. Detection of secreted and intracellular annexin II by a radioimmunoassay. J Immunol Methods. 1995 Dec 15;188(1):91–95. doi: 10.1016/0022-1759(95)00207-3. [DOI] [PubMed] [Google Scholar]
  5. Demange P., Voges D., Benz J., Liemann S., Göttig P., Berendes R., Burger A., Huber R. Annexin V: the key to understanding ion selectivity and voltage regulation? Trends Biochem Sci. 1994 Jul;19(7):272–276. doi: 10.1016/0968-0004(94)90002-7. [DOI] [PubMed] [Google Scholar]
  6. Drust D. S., Creutz C. E. Aggregation of chromaffin granules by calpactin at micromolar levels of calcium. Nature. 1988 Jan 7;331(6151):88–91. doi: 10.1038/331088a0. [DOI] [PubMed] [Google Scholar]
  7. Eberhard D. A., Brown M. D., VandenBerg S. R. Alterations of annexin expression in pathological neuronal and glial reactions. Immunohistochemical localization of annexins I, II (p36 and p11 subunits), IV, and VI in the human hippocampus. Am J Pathol. 1994 Sep;145(3):640–649. [PMC free article] [PubMed] [Google Scholar]
  8. Elderfield A. J., Newcombe J., Bolton C., Flower R. J. Lipocortins (annexins) 1, 2, 4 and 5 are increased in the central nervous system in multiple sclerosis. J Neuroimmunol. 1992 Jul;39(1-2):91–100. doi: 10.1016/0165-5728(92)90178-n. [DOI] [PubMed] [Google Scholar]
  9. Elsbach P., Weiss J. Bactericidal/permeability increasing protein and host defense against gram-negative bacteria and endotoxin. Curr Opin Immunol. 1993 Feb;5(1):103–107. doi: 10.1016/0952-7915(93)90088-a. [DOI] [PubMed] [Google Scholar]
  10. Evans T. C., Jr, Nelsestuen G. L. Calcium and membrane-binding properties of monomeric and multimeric annexin II. Biochemistry. 1994 Nov 15;33(45):13231–13238. doi: 10.1021/bi00249a009. [DOI] [PubMed] [Google Scholar]
  11. Flaherty M. J., West S., Heimark R. L., Fujikawa K., Tait J. F. Placental anticoagulant protein-I: measurement in extracellular fluids and cells of the hemostatic system. J Lab Clin Med. 1990 Feb;115(2):174–181. [PubMed] [Google Scholar]
  12. Flower R. J., Rothwell N. J. Lipocortin-1: cellular mechanisms and clinical relevance. Trends Pharmacol Sci. 1994 Mar;15(3):71–76. doi: 10.1016/0165-6147(94)90281-x. [DOI] [PubMed] [Google Scholar]
  13. Gazzano-Santoro H., Mészáros K., Birr C., Carroll S. F., Theofan G., Horwitz A. H., Lim E., Aberle S., Kasler H., Parent J. B. Competition between rBPI23, a recombinant fragment of bactericidal/permeability-increasing protein, and lipopolysaccharide (LPS)-binding protein for binding to LPS and gram-negative bacteria. Infect Immun. 1994 Apr;62(4):1185–1191. doi: 10.1128/iai.62.4.1185-1191.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gazzano-Santoro H., Parent J. B., Conlon P. J., Kasler H. G., Tsai C. M., Lill-Elghanian D. A., Hollingsworth R. I. Characterization of the structural elements in lipid A required for binding of a recombinant fragment of bactericidal/permeability-increasing protein rBPI23. Infect Immun. 1995 Jun;63(6):2201–2205. doi: 10.1128/iai.63.6.2201-2205.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gazzano-Santoro H., Parent J. B., Grinna L., Horwitz A., Parsons T., Theofan G., Elsbach P., Weiss J., Conlon P. J. High-affinity binding of the bactericidal/permeability-increasing protein and a recombinant amino-terminal fragment to the lipid A region of lipopolysaccharide. Infect Immun. 1992 Nov;60(11):4754–4761. doi: 10.1128/iai.60.11.4754-4761.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goulding N. J., Godolphin J. L., Sharland P. R., Peers S. H., Sampson M., Maddison P. J., Flower R. J. Anti-inflammatory lipocortin 1 production by peripheral blood leucocytes in response to hydrocortisone. Lancet. 1990 Jun 16;335(8703):1416–1418. doi: 10.1016/0140-6736(90)91445-g. [DOI] [PubMed] [Google Scholar]
  17. Goulding N. J., Guyre P. M. Glucocorticoids, lipocortins and the immune response. Curr Opin Immunol. 1993 Feb;5(1):108–113. doi: 10.1016/0952-7915(93)90089-b. [DOI] [PubMed] [Google Scholar]
  18. Heumann D., Gallay P., Le Roy D., Landmann R., Glauser M. P. Radioimmunoassay versus flow cytometric assay to quantify LPS-binding protein (LBP) concentrations in human plasma. J Immunol Methods. 1994 May 16;171(2):169–176. doi: 10.1016/0022-1759(94)90037-x. [DOI] [PubMed] [Google Scholar]
  19. Kaca W., Roth R. I., Levin J. Hemoglobin, a newly recognized lipopolysaccharide (LPS)-binding protein that enhances LPS biological activity. J Biol Chem. 1994 Oct 7;269(40):25078–25084. [PubMed] [Google Scholar]
  20. Kitchens R. L., Ulevitch R. J., Munford R. S. Lipopolysaccharide (LPS) partial structures inhibit responses to LPS in a human macrophage cell line without inhibiting LPS uptake by a CD14-mediated pathway. J Exp Med. 1992 Aug 1;176(2):485–494. doi: 10.1084/jem.176.2.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lorsbach R. B., Murphy W. J., Lowenstein C. J., Snyder S. H., Russell S. W. Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J Biol Chem. 1993 Jan 25;268(3):1908–1913. [PubMed] [Google Scholar]
  22. Lu Y., Bazzi M. D., Nelsestuen G. L. Kinetics of annexin VI, calcium, and phospholipid association and dissociation. Biochemistry. 1995 Aug 29;34(34):10777–10785. doi: 10.1021/bi00034a010. [DOI] [PubMed] [Google Scholar]
  23. McLeod J. D., Goodall A., Jelic P., Bolton C. Changes in the cellular distribution of lipocortin-1 (Annexin-1) in C6 glioma cells after exposure to dexamethasone. Biochem Pharmacol. 1995 Sep 28;50(7):1103–1107. doi: 10.1016/0006-2952(95)00234-q. [DOI] [PubMed] [Google Scholar]
  24. Meers P., Mealy T. Phospholipid determinants for annexin V binding sites and the role of tryptophan 187. Biochemistry. 1994 May 17;33(19):5829–5837. doi: 10.1021/bi00185a022. [DOI] [PubMed] [Google Scholar]
  25. Palmi M., Frosini M., Sgaragli G. P., Becherucci C., Perretti M., Parente L. Inhibition of interleukin-1 beta-induced pyresis in the rabbit by peptide 204-212 of lipocortin 5. Eur J Pharmacol. 1995 Jul 25;281(1):97–99. doi: 10.1016/0014-2999(95)00304-4. [DOI] [PubMed] [Google Scholar]
  26. Raynal P., Pollard H. B. Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins. Biochim Biophys Acta. 1994 Apr 5;1197(1):63–93. doi: 10.1016/0304-4157(94)90019-1. [DOI] [PubMed] [Google Scholar]
  27. Rietschel E. T., Kirikae T., Schade F. U., Mamat U., Schmidt G., Loppnow H., Ulmer A. J., Zähringer U., Seydel U., Di Padova F. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J. 1994 Feb;8(2):217–225. doi: 10.1096/fasebj.8.2.8119492. [DOI] [PubMed] [Google Scholar]
  28. Römisch J., Schüler E., Bastian B., Bürger T., Dunkel F. G., Schwinn A., Hartmann A. A., Pâques E. P. Annexins I to VI: quantitative determination in different human cell types and in plasma after myocardial infarction. Blood Coagul Fibrinolysis. 1992 Feb;3(1):11–17. [PubMed] [Google Scholar]
  29. Smith S. F., Tetley T. D., Datta A. K., Smith T., Guz A., Flower R. J. Lipocortin-1 distribution in bronchoalveolar lavage from healthy human lung: effect of prednisolone. J Appl Physiol (1985) 1995 Jul;79(1):121–128. doi: 10.1152/jappl.1995.79.1.121. [DOI] [PubMed] [Google Scholar]
  30. Solito E., Nuti S., Parente L. Dexamethasone-induced translocation of lipocortin (annexin) 1 to the cell membrane of U-937 cells. Br J Pharmacol. 1994 Jun;112(2):347–348. doi: 10.1111/j.1476-5381.1994.tb13075.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stone R. Search for sepsis drugs goes on despite past failures. Science. 1994 Apr 15;264(5157):365–367. doi: 10.1126/science.8153620. [DOI] [PubMed] [Google Scholar]
  32. Thorin B., Gache G., Dubois T., Grataroli R., Domingo N., Russo-Marie F., Lafont H. Annexin VI is secreted in human bile. Biochem Biophys Res Commun. 1995 Apr 26;209(3):1039–1045. doi: 10.1006/bbrc.1995.1602. [DOI] [PubMed] [Google Scholar]
  33. Tobias P. S., Soldau K., Ulevitch R. J. Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. J Biol Chem. 1989 Jun 25;264(18):10867–10871. [PubMed] [Google Scholar]
  34. Tressler R. J., Updyke T. V., Yeatman T., Nicolson G. L. Extracellular annexin II is associated with divalent cation-dependent tumor cell-endothelial cell adhesion of metastatic RAW117 large-cell lymphoma cells. J Cell Biochem. 1993 Nov;53(3):265–276. doi: 10.1002/jcb.240530311. [DOI] [PubMed] [Google Scholar]
  35. Uemura K., Inagaki H., Wada Y., Nakanishi K., Asai K., Kato T., Ando Y., Kannagi R. Identification of immuno-reactive lipocortin 1-like molecules in serum and plasma by an enzyme immunoassay for lipocortin 1. Biochim Biophys Acta. 1992 Mar 12;1119(3):250–255. doi: 10.1016/0167-4838(92)90210-5. [DOI] [PubMed] [Google Scholar]
  36. Ulevitch R. J., Tobias P. S. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol. 1995;13:437–457. doi: 10.1146/annurev.iy.13.040195.002253. [DOI] [PubMed] [Google Scholar]
  37. Ulvestad E., Kristoffersen E. K., Jensen T. S., Matre R. Identification of a soluble Fc gamma-binding molecule (annexin II) in human serum using a competitive ELISA. APMIS. 1994 Sep;102(9):667–673. doi: 10.1111/j.1699-0463.1994.tb05218.x. [DOI] [PubMed] [Google Scholar]
  38. Vergnolle N., Coméra C., Buéno L. Annexin 1 is overexpressed and specifically secreted during experimentally induced colitis in rats. Eur J Biochem. 1995 Sep 1;232(2):603–610. doi: 10.1111/j.1432-1033.1995.tb20850.x. [DOI] [PubMed] [Google Scholar]
  39. Wang W., Creutz C. E. Role of the amino-terminal domain in regulating interactions of annexin I with membranes: effects of amino-terminal truncation and mutagenesis of the phosphorylation sites. Biochemistry. 1994 Jan 11;33(1):275–282. doi: 10.1021/bi00167a036. [DOI] [PubMed] [Google Scholar]
  40. Weiss J., Beckerdite-Quagliata S., Elsbach P. Resistance of gram-negative bacteria to purified bactericidal leukocyte proteins: relation to binding and bacterial lipopolysaccharide structure. J Clin Invest. 1980 Mar;65(3):619–628. doi: 10.1172/JCI109707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wilde C. G., Seilhamer J. J., McGrogan M., Ashton N., Snable J. L., Lane J. C., Leong S. R., Thornton M. B., Miller K. L., Scott R. W. Bactericidal/permeability-increasing protein and lipopolysaccharide (LPS)-binding protein. LPS binding properties and effects on LPS-mediated cell activation. J Biol Chem. 1994 Jul 1;269(26):17411–17416. [PubMed] [Google Scholar]
  42. Wu C. C., Croxtall J. D., Perretti M., Bryant C. E., Thiemermann C., Flower R. J., Vane J. R. Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3473–3477. doi: 10.1073/pnas.92.8.3473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wurfel M. M., Wright S. D. Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Prog Clin Biol Res. 1995;392:287–295. [PubMed] [Google Scholar]
  44. Yeatman T. J., Updyke T. V., Kaetzel M. A., Dedman J. R., Nicolson G. L. Expression of annexins on the surfaces of non-metastatic and metastatic human and rodent tumor cells. Clin Exp Metastasis. 1993 Jan;11(1):37–44. doi: 10.1007/BF00880064. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES