Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1985 May 1;161(5):1013–1028. doi: 10.1084/jem.161.5.1013

Impaired Kupffer cell function precedes development of secondary amyloidosis

PMCID: PMC2187597  PMID: 3989470

Abstract

It has been demonstrated previously that the acute phase reactant, serum amyloid A (SAA), is subject to degradation by surface membrane- associated proteinases of peripheral blood monocytes. However, monocytes obtained from the blood of patients with amyloidosis degraded SAA incompletely, leaving a cleavage product that, biochemically and immunologically, resembled the amyloid protein A (AA) deposited in their tissues. To investigate the role of fixed macrophages in amyloidogenesis and to establish more definitively that amyloid deposition is attributable to faulty processing of the precursor protein rather than aberrant synthesis, secondary amyloidosis was induced in C57BL/6J mice by serial injections of casein. Kupffer cells (KC) were isolated from livers of mice that had received 0, 8, 13, 18, and greater than 30 injections of the stimulant. The cells were cultured with SAA for 4, 8, and 18 h and then subjected to electron microscopy and enzyme analyses. The medium was analyzed by SDS-PAGE to determine the amount of residual SAA and/or the appearance of AA. KC of healthy animals degraded SAA completely whereas KC of stimulated mice showed increasing amounts of residual SAA and the appearance of the AA cleavage product. The AA peptide appeared in KC cultures early during the course of casein injections and before any amyloid could be demonstrated in the organs of the stimulated mice. The addition of KC isolated from healthy mice to cultures that had produced AA eliminated the abnormal peptide. The results, indicate that defective KC function precedes amyloidosis. The abnormal AA cleavage product formed by such cells is still susceptible to hydrolysis by normal cells. In addition, ultrastructural evidence is presented that suggests that KC may also play a role in fibrillogenesis of the AA protein.

Full Text

The Full Text of this article is available as a PDF (2.9 MB).

Selected References

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

  1. BATTAGLIA S. [Electronoptic studies on liver amyloid in mice]. Beitr Pathol Anat. 1962 Jun;126:300–320. [PubMed] [Google Scholar]
  2. BATTAGLIA S. [On amyloid genesis]. Klin Wochenschr. 1961 Aug 1;39:795–798. doi: 10.1007/BF01482097. [DOI] [PubMed] [Google Scholar]
  3. Beguinot L., Lyall R. M., Willingham M. C., Pastan I. Down-regulation of the epidermal growth factor receptor in KB cells is due to receptor internalization and subsequent degradation in lysosomes. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2384–2388. doi: 10.1073/pnas.81.8.2384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohn Z. A. Activation of mononuclear phagocytes: fact, fancy, and future. J Immunol. 1978 Sep;121(3):813–816. [PubMed] [Google Scholar]
  5. Costa P. P., Figueira A. S., Bravo F. R. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4499–4503. doi: 10.1073/pnas.75.9.4499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cotter T. G., Robinson G. B. Purification and characterisation of an 'elastase-like' enzyme from rabbit polymorphonuclear leucocytes. Biochim Biophys Acta. 1980 Oct;615(2):414–425. doi: 10.1016/0005-2744(80)90508-2. [DOI] [PubMed] [Google Scholar]
  7. Edelson P. J., Cohn Z. A. 5'-Nucleotidase activity of mouse peritoneal macrophages. I. Synthesis and degradation in resident and inflammatory populations. J Exp Med. 1976 Dec 1;144(6):1581–1595. doi: 10.1084/jem.144.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Edelson P. J., Cohn Z. A. 5'-Nucleotidase activity of mouse peritoneal macrophages. II. Cellular distribution and effects of endocytosis. J Exp Med. 1976 Dec 1;144(6):1596–1608. doi: 10.1084/jem.144.6.1596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Emeis J. J. Morphologic and cytochemical heterogeneity of the cell coat of rat liver Kupffer cells. J Reticuloendothel Soc. 1976 Jul;20(1):31–50. [PubMed] [Google Scholar]
  10. Eriksen N., Ericsson L. H., Pearsall N., Lagunoff D., Benditt E. P. Mouse amyloid protein AA: Homology with nonimmunoglobulin protein of human and monkey amyloid substance. Proc Natl Acad Sci U S A. 1976 Mar;73(3):964–967. doi: 10.1073/pnas.73.3.964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Franklin E. C., Zucker-Franklin D. Current concepts of amyloid. Adv Immunol. 1972;15:249–304. doi: 10.1016/s0065-2776(08)60687-2. [DOI] [PubMed] [Google Scholar]
  12. Fuks A., Zucker-Franklin D., Franklin E. C. Identification of elastases associated with purified plasma membranes isolated from human monocytes and lymphocytes. Biochim Biophys Acta. 1983 Jan 25;755(2):195–203. doi: 10.1016/0304-4165(83)90203-9. [DOI] [PubMed] [Google Scholar]
  13. GUEFT B., GHIDONI J. J. THE SITE OF FORMATION AND ULTRASTRUCTURE OF AMYLOID. Am J Pathol. 1963 Nov;43:837–854. [PMC free article] [PubMed] [Google Scholar]
  14. Gafni J., Ravid M., Sohar E. The role of amyloidosis in familial mediterranean fever. A population study. Isr J Med Sci. 1968 Sep-Oct;4(5):995–999. [PubMed] [Google Scholar]
  15. Glenner G. G. Amyloid deposits and amyloidosis: the beta-fibrilloses (second of two parts). N Engl J Med. 1980 Jun 12;302(24):1333–1343. doi: 10.1056/NEJM198006123022403. [DOI] [PubMed] [Google Scholar]
  16. Gorevic P. D., Rosenthal C. J., Franklin E. C. Amyloid-related serum component (SAA)--studies in acute infections, medullary thyroid carcinoma, and postsurgery. Clin Immunol Immunopathol. 1976 Jul;6(1):83–93. doi: 10.1016/0090-1229(76)90063-5. [DOI] [PubMed] [Google Scholar]
  17. Hoffman J. S., Ericsson L. H., Eriksen N., Walsh K. A., Benditt E. P. Murine tissue amyloid protein AA. NH2-terminal sequence identity with only one of two serum amyloid protein (ApoSAA) gene products. J Exp Med. 1984 Feb 1;159(2):641–646. doi: 10.1084/jem.159.2.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. KAPLOW L. S. SIMPLIFIED MYELOPEROXIDASE STAIN USING BENZIDINE DIHYDROCHLORIDE. Blood. 1965 Aug;26:215–219. [PubMed] [Google Scholar]
  19. Knook D. L., Sleyster E. C., Teutsch H. F. High activity of glucose-6-phosphate dehydrogenase in Kupffer cells isolated from rat liver. Histochemistry. 1980;69(2):211–216. doi: 10.1007/BF00533138. [DOI] [PubMed] [Google Scholar]
  20. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  21. Lavie G., Zucker-Franklin D., Franklin E. C. Degradation of serum amyloid A protein by surface-associated enzymes of human blood monocytes. J Exp Med. 1978 Oct 1;148(4):1020–1031. doi: 10.1084/jem.148.4.1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lavie G., Zucker-Franklin D., Franklin E. C. Elastase-type proteases on the surface of human blood monocytes: possible role in amyloid formation. J Immunol. 1980 Jul;125(1):175–180. [PubMed] [Google Scholar]
  23. Levin M., Franklin E. C., Frangione B., Pras M. The amino acid sequence of a major nonimmunoglobulin component of some amyloid fibrils. J Clin Invest. 1972 Oct;51(10):2773–2776. doi: 10.1172/JCI107098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Levin M., Pras M., Franklin E. C. Immunologic studies of the major nonimmunoglobulin protein of amyloid. I. Identification and partial characterization of a related serum component. J Exp Med. 1973 Aug 1;138(2):373–380. doi: 10.1084/jem.138.2.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li C. Y., Lam K. W., Yam L. T. Esterases in human leukocytes. J Histochem Cytochem. 1973 Jan;21(1):1–12. doi: 10.1177/21.1.1. [DOI] [PubMed] [Google Scholar]
  26. Lorand L., Weissmann L. B., Epel D. L., Bruner-Lorand J. Role of the intrinsic transglutaminase in the Ca2+-mediated crosslinking of erythrocyte proteins. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4479–4481. doi: 10.1073/pnas.73.12.4479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McAdam K. P., Sipe J. D. Murine model for human secondary amyloidosis: genetic variability of the acute-phase serum protein SAA response to endotoxins and casein. J Exp Med. 1976 Oct 1;144(4):1121–1127. doi: 10.1084/jem.144.4.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McAdam K. P., Sipe J. D. Murine model for human secondary amyloidosis: genetic variability of the acute-phase serum protein SAA response to endotoxins and casein. J Exp Med. 1976 Oct 1;144(4):1121–1127. doi: 10.1084/jem.144.4.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mills D. M., Zucker-Franklin D. Electron microscopic study of isolated Kupffer cells. Am J Pathol. 1969 Feb;54(2):147–166. [PMC free article] [PubMed] [Google Scholar]
  30. Puchtler H., Sweat F. Congo red as a stain for fluorescence microscopy of amyloid. J Histochem Cytochem. 1965 Nov-Dec;13(8):693–694. doi: 10.1177/13.8.693. [DOI] [PubMed] [Google Scholar]
  31. Ranlov P., Wanstrup J. Ultrastructural investigations on the cellular morphogenesis of experimental mouse amyloidosis. Acta Pathol Microbiol Scand. 1967;71(4):575–591. doi: 10.1111/j.1699-0463.1967.tb05178.x. [DOI] [PubMed] [Google Scholar]
  32. Rosenthal C. J., Franklin E. C. Age-associated changes of an amyloid related serum component. Trans Assoc Am Physicians. 1974;87:159–168. [PubMed] [Google Scholar]
  33. Rosenthal C. J., Franklin E. C., Frangione B., Greenspan J. Isolation and partial characterization of SAA-an amyloid-related protein from human serum. J Immunol. 1976 May;116(5):1415–1418. [PubMed] [Google Scholar]
  34. SHEARING S. P., COMERFORD F. R., COHEN A. S. EFFECT OF AN AMYLOID INDUCING REGIMEN ON PHAGOCYTOSIS OF CARBON PARTICLES. Proc Soc Exp Biol Med. 1965 Jul;119:673–676. doi: 10.3181/00379727-119-30268. [DOI] [PubMed] [Google Scholar]
  35. Selinger M. J., McAdam K. P., Kaplan M. M., Sipe J. D., Vogel S. N., Rosenstreich D. L. Monokine-induced synthesis of serum amyloid A protein by hepatocytes. Nature. 1980 Jun 12;285(5765):498–500. doi: 10.1038/285498a0. [DOI] [PubMed] [Google Scholar]
  36. Simon M., Green H. Participation of membrane-associated proteins in the formation of the cross-linked envelope of the keratinocyte. Cell. 1984 Apr;36(4):827–834. doi: 10.1016/0092-8674(84)90032-1. [DOI] [PubMed] [Google Scholar]
  37. Skinner M., Shirahama T., Benson M. D., Cohen A. S. Murine amyloid protein AA in casein-induced experimental amyloidosis. Lab Invest. 1977 Apr;36(4):420–427. [PubMed] [Google Scholar]
  38. Sletten K., Westermark P., Natvig J. B. Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid. J Exp Med. 1976 Apr 1;143(4):993–998. doi: 10.1084/jem.143.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. TEILUM G. PATHOGENESIS OF AMYLOIDOSIS. Acta Pathol Microbiol Scand. 1964;61:21–45. doi: 10.1111/apm.1964.61.1.21. [DOI] [PubMed] [Google Scholar]
  40. Zemer D., Pras M., Sohar E., Gafni J. Letter: Colchicine in familial Mediterranean fever. N Engl J Med. 1976 Jan 15;294(3):170–171. doi: 10.1056/NEJM197601152940327. [DOI] [PubMed] [Google Scholar]
  41. Zucker-Franklin D., Grusky G., Marcus A. Transformation of monocytes into "fat" cells. Lab Invest. 1978 May;38(5):620–628. [PubMed] [Google Scholar]
  42. Zucker-Franklin D. Immunophagocytosis of human amyloid fibrils by leukocytes. J Ultrastruct Res. 1970 Aug;32(3):247–257. doi: 10.1016/s0022-5320(70)80005-3. [DOI] [PubMed] [Google Scholar]
  43. Zucker-Franklin D., Lavie G., Franklin E. C. Demonstration of membrane-bound proteolytic activity on the surface of mononuclear leukocytes. J Histochem Cytochem. 1981 Mar;29(3A):451–456. doi: 10.1177/29.3.451. [DOI] [PubMed] [Google Scholar]

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

RESOURCES