Impaired Kupffer cell function precedes development of secondary amyloidosis.
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.
D000686:Amyloidosis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D000818:Animals; D002364:Caseins; D002469:Cell Separation; D006651:Histocytochemistry; D007728:Kupffer Cells / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000685:Serum Amyloid A Protein / Q000096:biosynthesis / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D002364:Caseins; D000685:Serum Amyloid A Protein