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Hemodialysis-related induction of beta-2-microglobulin and interleukin-1 synthesis and release by mononuclear
1Department of Pathology, Columbia University, College of Physicians and Surgeons, New York.
Abstract:
We have investigated beta 2-microglobulin (beta 2M) synthesis and release by blood leukocytes and isolated mononuclear phagocytes. Recent interest in beta 2M 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 beta 2M in their circulation. Since hemodialysis-related factors that increase beta 2M production are unknown, we evaluated beta 2M production by freshly prepared leukocytes and monocyte-derived macrophages under a variety of conditions. We utilized a novel enzyme-linked immunoabsorbant assay to quantitate beta 2M concentrations, and monitored interleukin-1 and beta 2M synthesis by immunoprecipitation. Incubation of leukocytes with Cuprophan or Hemophan does not increase beta 2M release. Adherence of macrophages onto polystyrene or Cuprophan membranes induces neither interleukin-1 nor beta 2M synthesis or release. In contrast, interaction of macrophages with lipopolysaccharide, gamma-interferon, tumor necrosis factor, or interleukin-1 induces synthesis and release of beta 2 M, indicating that beta 2 M synthesis is increased during macrophage activation. Exposing leukocytes or macrophages to changes in osmotic or oncotic pressure induces a rapid release of beta 2M and interleukin-1 into the cellular medium. These results suggest that during hemodialysis, beta 2M production is more likely to result from endotoxin contamination, or osmotic and oncotic changes, rather than direct interaction of mononuclear phagocytes with Cuprophan membranes.
Insights
Beta 2-microglobulin (beta 2M) release from leukocytes is not caused by hemodialysis membranes. Instead, osmotic changes or endotoxin contamination during dialysis likely increase beta 2M production in patients.
Area of Science:
- Immunology
- Nephrology
- Biochemistry
Background:
- Elevated beta 2-microglobulin (beta 2M) levels are observed in patients undergoing chronic hemodialysis.
- Beta 2M can form amyloid fibrils, leading to dialysis-related amyloidosis.
- The factors driving increased beta 2M production during hemodialysis are not fully understood.
Purpose of the Study:
- To investigate the synthesis and release of beta 2-microglobulin (beta 2M) by blood leukocytes and mononuclear phagocytes.
- To determine the specific conditions that stimulate beta 2M production in vitro.
- To identify potential causes for elevated beta 2M levels in hemodialysis patients.
Main Methods:
- Quantification of beta 2M concentrations using a novel enzyme-linked immunosorbent assay (ELISA).
- Monitoring of interleukin-1 and beta 2M synthesis via immunoprecipitation.
- Incubation of leukocytes and macrophages with various stimuli, including hemodialysis membranes (Cuprophan, Hemophan), polystyrene, lipopolysaccharide, cytokines, and osmotic/oncotic pressure changes.
Main Results:
- Incubation with Cuprophan or Hemophan membranes did not increase beta 2M release from leukocytes.
- Macrophage adherence to polystyrene or Cuprophan did not induce beta 2M or interleukin-1 synthesis.
- Macrophage activation by lipopolysaccharide, gamma-interferon, tumor necrosis factor, or interleukin-1 significantly increased beta 2M synthesis and release.
- Rapid release of beta 2M and interleukin-1 was observed when leukocytes or macrophages were exposed to osmotic or oncotic pressure changes.
Conclusions:
- Direct interaction with hemodialysis membranes (Cuprophan, Hemophan) is unlikely to be the primary cause of increased beta 2M production.
- Macrophage activation, triggered by factors like endotoxin contamination, is a significant driver of beta 2M synthesis.
- Osmotic and oncotic pressure variations during hemodialysis may contribute to the rapid release of beta 2M and interleukin-1.