IMPAIRED ENDOTOXIN-INDUCED INTERLEUKIN-1-BETA SECRETION, NOT TOTAL PRODUCTION, OF MONONUCLEAR-CELLS FROM ESRD PATIENTS

Lipopolysaccharide (LPS)-induced interleukin-1 beta (IL-1 beta) and tu mor necrosis factor alpha (TNF alpha) production and secretion from pe ripheral blood mononuclear cells (PBMC) were determined in a longitudi nal study with repeated measurements in PBMC from patients with chroni c uremia not on hemodialysis (N = 8), end-stage renal disease (ESRD) p atients (N = 8), and healthy controls (N = 7). ESRD patients were stud ied while using low-flux Cuprophan dialyzers and again using high-flux AN 69 dialyzers. Total (cell-associated plus secreted) LPS-induced IL -1 beta production was enhanced in uremic patients, but similar to con trols in ESRD patients on Cuprophan. In contrast, LPS-induced IL-1 bet a secretion (secreted amounts in % of total production) was similar to controls in uremic patients, but significantly reduced in ESRD patien ts on Cuprophan (P < 0.01). During AN 69 hemodialysis, LPS-induced tot al IL-1 beta production remained unchanged but IL-1 beta secretion inc reased significantly (P < 0.05) compared to Cuprophan dialysis. Increa sed IL-1 beta secretion coincided with a suppression in PGE(2) synthes is (P < 0.02). Similarly, blockade of endogenous PGE(2) by indomethaci n increased LPS-induced IL-1 beta secretion (P ( 0.01) but did not enh ance total IL-1 beta production in PBMC from controls and patients on Cuprophan hemodialysis. Neither total production nor secretion of TNF alpha was different comparing the three study groups. We conclude that LPS-induced IL-1 beta secretion, but not total production, is impaire d in PBMC from ESRD patients on long-term Cuprophan hemodialysis. This functional change in the PBMC response is specific for IL-1 beta, not due to uremia per se but hemodialysis-dependent and reversible. Hemod ialysis with AN 69 suppresses endogenous PGE(2) synthesis in PBMC whic h is associated with increased LPS-induced IL-1 beta secretion in the presence of unchanged total IL-1 beta production. We speculate that PG E(2) could inactivate the IL-1 beta converting enzyme which is essenti al for processing and secretion of mature IL-1 beta.