Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1993 Feb 15;290(Pt 1):109–113. doi: 10.1042/bj2900109

The hepatic acute-phase proteins alpha 1-antitrypsin and alpha 2-macroglobulin inhibit binding of transferrin to its receptor.

I Graziadei 1, R Kaserbacher 1, H Braunsteiner 1, W Vogel 1
PMCID: PMC1132388  PMID: 7679893

Abstract

Transferrin binding to human placental sites was inhibited by the acute-phase proteins alpha 1-antitrypsin (alpha 1-AT) and alpha 2-macroglobulin (alpha 2-MG), whereas haptoglobin, C-reactive protein and ferritin displayed no such effect. In equilibrium saturation binding assays, the effective acute-phase proteins decreased the apparent affinity of the binding sites for transferrin, but the transferrin binding-site density Bmax. was not significantly changed. For instance, the addition of 30 microM alpha 1-AT increased the KD of transferrin from 8.46 +/- 1.51 nM to 21.6 +/- 3.04 nM; the Bmax. values were 1.17 +/- 0.18 pmol/mg of protein and 1.04 +/- 0.25 pmol/mg of protein respectively. In kinetic studies, alpha 1-AT decreased the association rate constant k+1 of the 125I-transferrin-binding-site complex from 2.18(+/- 0.21) x 10(7) M-1.min-1 to 3.99(+/- 0.18) x 10(6) M-1.min-1. In contrast, the dissociation rate constant k-1 was not changed (0.0948 +/- 0.002 min-1, 0.089 +/- 0.0017 min-1). On isoelectric focusing, no alteration in transferrin protein pattern or shift in isoelectric point was detected in the presence of alpha 1-AT. Inhibition of transferrin binding by the acute-phase proteins alpha 1-AT and alpha 2-MG is competitive. Interestingly, inhibition is already present at physiological concentrations. However, full inhibition is only achieved at concentrations above the normal range, which are attained in acute-phase reactions.

Full text

PDF
109

Images in this article

112Figure 4
on p.112

Selected References

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

  1. Aisen P., Brown E. B. Structure and function of transferrin. Prog Hematol. 1975;9:25–56. [PubMed] [Google Scholar]
  2. Anderson G. J., Mackerras A., Powell L. W., Halliday J. W. Improved purification of the human placental transferrin receptor and a novel immunoradiometric assay for receptor protein. Biochim Biophys Acta. 1986 Nov 19;884(2):225–233. doi: 10.1016/0304-4165(86)90167-4. [DOI] [PubMed] [Google Scholar]
  3. Andus T., Bauer J., Gerok W. Effects of cytokines on the liver. Hepatology. 1991 Feb;13(2):364–375. [PubMed] [Google Scholar]
  4. Andus T., Geiger T., Hirano T., Kishimoto T., Tran-Thi T. A., Decker K., Heinrich P. C. Regulation of synthesis and secretion of major rat acute-phase proteins by recombinant human interleukin-6 (BSF-2/IL-6) in hepatocyte primary cultures. Eur J Biochem. 1988 Apr 15;173(2):287–293. doi: 10.1111/j.1432-1033.1988.tb13997.x. [DOI] [PubMed] [Google Scholar]
  5. Bomford A., Isaac J., Roberts S., Edwards A., Young S., Williams R. The effect of desferrioxamine on transferrin receptors, the cell cycle and growth rates of human leukaemic cells. Biochem J. 1986 May 15;236(1):243–249. doi: 10.1042/bj2360243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Breit S. N., Robinson J. P., Penny R. The effect of alpha 1 antitrypsin on phagocyte function. J Clin Lab Immunol. 1983 Mar;10(3):147–149. [PubMed] [Google Scholar]
  7. Carrell R. W., Jeppsson J. O., Laurell C. B., Brennan S. O., Owen M. C., Vaughan L., Boswell D. R. Structure and variation of human alpha 1-antitrypsin. Nature. 1982 Jul 22;298(5872):329–334. doi: 10.1038/298329a0. [DOI] [PubMed] [Google Scholar]
  8. Castell J. V., Gómez-Lechón M. J., David M., Andus T., Geiger T., Trullenque R., Fabra R., Heinrich P. C. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 1989 Jan 2;242(2):237–239. doi: 10.1016/0014-5793(89)80476-4. [DOI] [PubMed] [Google Scholar]
  9. Crystal R. G. Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy. J Clin Invest. 1990 May;85(5):1343–1352. doi: 10.1172/JCI114578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davies M., Parry J. E., Sutcliffe R. G. Examination of different preparations of human placental plasma membrane for the binding of insulin, transferrin and immunoglobulins. J Reprod Fertil. 1981 Nov;63(2):315–324. doi: 10.1530/jrf.0.0630315. [DOI] [PubMed] [Google Scholar]
  11. Deiss A. Iron metabolism in reticuloendothelial cells. Semin Hematol. 1983 Apr;20(2):81–90. [PubMed] [Google Scholar]
  12. Dinarello C. A. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984 Nov 29;311(22):1413–1418. doi: 10.1056/NEJM198411293112205. [DOI] [PubMed] [Google Scholar]
  13. Farrow S. P., Baar S. The metabolism of alpha2-macroglobulin in mildly burned patients. Clin Chim Acta. 1973 Jun 14;46(1):39–48. doi: 10.1016/0009-8981(73)90100-9. [DOI] [PubMed] [Google Scholar]
  14. Frazier J. L., Caskey J. H., Yoffe M., Seligman P. A. Studies of the transferrin receptor on both human reticulocytes and nucleated human cells in culture: comparison of factors regulating receptor density. J Clin Invest. 1982 Apr;69(4):853–865. doi: 10.1172/JCI110525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Geiger T., Andus T., Klapproth J., Hirano T., Kishimoto T., Heinrich P. C. Induction of rat acute-phase proteins by interleukin 6 in vivo. Eur J Immunol. 1988 May;18(5):717–721. doi: 10.1002/eji.1830180510. [DOI] [PubMed] [Google Scholar]
  16. Graziadei I., Zernig G., Boer R., Glossman H. Stereoselective binding of niguldipine enantiomers to alpha 1A-adrenoceptors labeled with [3H]5-methyl-urapidil. Eur J Pharmacol. 1989 Oct 17;172(4-5):329–337. doi: 10.1016/0922-4106(89)90013-8. [DOI] [PubMed] [Google Scholar]
  17. Huebers H. A., Finch C. A. The physiology of transferrin and transferrin receptors. Physiol Rev. 1987 Apr;67(2):520–582. doi: 10.1152/physrev.1987.67.2.520. [DOI] [PubMed] [Google Scholar]
  18. JANDL J. H., KATZ J. H. The plasma-to-cell cycle of transferrin. J Clin Invest. 1963 Mar;42:314–326. doi: 10.1172/JCI104718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koj A., Gauldie J., Regoeczi E., Sauder D. N., Sweeney G. D. The acute-phase response of cultured rat hepatocytes. System characterization and the effect of human cytokines. Biochem J. 1984 Dec 1;224(2):505–514. doi: 10.1042/bj2240505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  21. MacGillivray R. T., Mendez E., Sinha S. K., Sutton M. R., Lineback-Zins J., Brew K. The complete amino acid sequence of human serum transferrin. Proc Natl Acad Sci U S A. 1982 Apr;79(8):2504–2508. doi: 10.1073/pnas.79.8.2504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pascali V. L., Dobosz M., Destro-Bisol G., D'Aloja E. Characterization of genetic variants of human serum transferrin by isoelectric focusing: comparison between conventional and immobilized pH gradients, and application to a protocol for paternity testing. Electrophoresis. 1988 Aug;9(8):411–417. doi: 10.1002/elps.1150090811. [DOI] [PubMed] [Google Scholar]
  23. Penhallow R. C., Mason A. B., Woodworth R. C. Electrophoretic characterization of human, equine and bovine transferrins. Comp Biochem Physiol B. 1991;98(1):41–45. doi: 10.1016/0305-0491(91)90305-w. [DOI] [PubMed] [Google Scholar]
  24. Perlmutter D. H., Dinarello C. A., Punsal P. I., Colten H. R. Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest. 1986 Nov;78(5):1349–1354. doi: 10.1172/JCI112721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Perlmutter D. H., May L. T., Sehgal P. B. Interferon beta 2/interleukin 6 modulates synthesis of alpha 1-antitrypsin in human mononuclear phagocytes and in human hepatoma cells. J Clin Invest. 1989 Jul;84(1):138–144. doi: 10.1172/JCI114133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Robey F. A., Jones K. D., Tanaka T., Liu T. Y. Binding of C-reactive protein to chromatin and nucleosome core particles. A possible physiological role of C-reactive protein. J Biol Chem. 1984 Jun 10;259(11):7311–7316. [PubMed] [Google Scholar]
  27. Titus R. G., Sherry B., Cerami A. The involvement of TNF, IL-1 and IL-6 in the immune response to protozoan parasites. Immunol Today. 1991 Mar;12(3):A13–A16. doi: 10.1016/S0167-5699(05)80005-2. [DOI] [PubMed] [Google Scholar]
  28. Travis J. Structure, function, and control of neutrophil proteinases. Am J Med. 1988 Jun 24;84(6A):37–42. doi: 10.1016/0002-9343(88)90156-8. [DOI] [PubMed] [Google Scholar]
  29. Trowbridge I. S., Newman R. A., Domingo D. L., Sauvage C. Transferrin receptors: structure and function. Biochem Pharmacol. 1984 Mar 15;33(6):925–932. doi: 10.1016/0006-2952(84)90447-7. [DOI] [PubMed] [Google Scholar]
  30. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  31. Vogel W., Bomford A., Young S., Williams R. Heterogeneous distribution of transferrin receptors on parenchymal and nonparenchymal liver cells: biochemical and morphological evidence. Blood. 1987 Jan;69(1):264–270. [PubMed] [Google Scholar]

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

RESOURCES