Impaired endotoxin-induced interleukin-1β secretion, not total production, of mononuclear cells from ESRD patients

Abstract

Lipopolysaccharide (LPS)-induced interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) production and secretion from peripheral blood mononuclear cells (PBMC) were determined in a longitudinal study with repeated measurements in PBMC from patients with chronic uremia not on hemodialysis (N = 8), end-stage renal disease (ESRD) patients (N = 8), and healthy controls (N = 7). ESRD patients were studied while using low-flux Cuprophan dialyzers and again using high-flux AN 69 dialyzers. Total (cell-associated plus secreted) LPS-induced IL-1β production was enhanced in uremic patients, but similar to controls in ESRD patients on Cuprophan. In contrast, LPS-induced IL-1β secretion (secreted amounts in % of total production) was similar to controls in uremic patients, but sisnificantly reduced in ESRD patients on Cuprophan (P < 0.01). During AN 69 hemodialysis, LPS-induced total IL-1β production remained nchansed but IL-1β secretion increased significantly (P < 0.05) compared to Cuprophan dialysis. Increased IL-1β secretion coincided with a suppression in PGE2 synthesis (P < 0.02). Similarly, blockade of endog enous PGE2 by indomethacin increased LPS-induced IL-1β secretion (P < 0.01) but did not enhance total IL-1β production in PBMC from controls and patients on Cuprophan hemodialysis. Neither total production nor secretion of TNFα was different comparing the three study groups. We conclude that LPS-induced IL-β secretion, but not total production, is impaired in PBMC from ESRD patients on long-term Cuprophan hemodialysis. This functional change in the PBMC response is spccific for IL-1β, not due to uremia per se but hemodialysis-dependent and reversible. Hemodialysis with AN 69 suppresses endogenous PGE2 synthesis in PBMC which is associated with increased LPS-induced IL-1β secretion in the presence of unchanged total IL-1β production. We speculate that PGE2 could inactivate the IL-1β converting enzyme which is essential for processing and secretion of mature IL-1β.