Hemodialysis-Related Induction of Beta-2-Microglobulin and Interleukin-1 Synthesis and Release by Mononuclear Phagocytes

Abstract

We have investigated β₂-microglobulin (β₂M) synthesis and release by blood leukocytes and isolated mononuclear phagocytes. Recent interest in β₂M has developed since the discovery that this protein forms amyloid fibrils in patients undergoing long-term, chronic hemodialysis and that these patients have greatly elevated levels of monomeric β₂M in their circulation. Since hemodialysis-related factors that increase β₂M production are unknown, we evaluated β₂M production by freshly prepared leukocytes and monocyte-derived macrophages under a variety of conditions. We utilized a novel enzyme-linked immunoabsorbant assay to quantitate β₂M concentrations, and monitored interleukin-1 and β₂M synthesis by immunoprecipitation. Incubation of leukocytes with Cuprophan or Hemophan does not increase β₂M release. Adherence of macrophages onto polystyrene or Cuprophan membranes induces neither interleukin-1 nor β₂M synthesis or release. In contrast, interaction of macrophages with lipopolysaccharide, γ-interferon, tumor necrosis factor, or interleukin-1 induces synthesis and release of β₂M, indicating that β₂M synthesis is increased during macrophage activation. Exposing leukocytes or macrophages to changes in osmotic or oncotic pressure induces a rapid release of β₂M and interleukin-1 into the cellular medium. These results suggest that during hemodialysis, β₂M production is more likely to result from endotoxin contamination, or osmotic and oncotic changes, rather than direct interaction of mononuclear phagocytes with Cuprophan membranes.

Increased Binding of Beta-2-Microglobulin to Blood Cells in Dialysis Patients Treated with High-Flux Dialyzers Compared with Low-Flux Membranes Contributed to Reduced Beta-2-Microglobulin Concentrations

“…However, we found no difference between low-and high-flux membranes on ␤ 2 -microglobulin mRNA expression in whole blood despite the fact that increases in c-fos and TNF-␣ mRNA expression in patients on low-flux dialyzers indicated cell activation. These findings are in agreement with earlier in vitro studies by Knudsen et al demonstrating that ␤ 2 -microglobulin synthesis in blood cells is stimulated by endotoxins, but not by adherence to cuprophan dialyzer membranes [20] . This would also support clinical observations that the quality of the water is more important for the plasma ␤ 2 -microglobulin concentrations than the type of dialyzer membrane used [8,21] .…”

Reduction of Neutrophil Activation by Vitamin E Modified Dialyzer Membranes

“…Mitzner et al [27]reported an increased expression of soluble CD14, a receptor for lipopolysaccharide, in clinical HD. Induction of interleukin 1 synthesis and beta-2-microglobulin production during clinical HD also have been reported [28, 29]. These findings suggest that biological reactions in clinical HD are caused in part by transmembranous contact with bacterial products or nonphysiological substances in the dialysate.…”

Imbalance of Oxidants and Antioxidants in Haemodialysis Patients

“…There is increasing evidence suggesting that presence of lipopolysaccharide (LPS) in the dialysate may activate blood monocytes/macrophages through the dialyser membrane contributing to cytokine release and free oxygen radical production [36,37].…”