Pro-inflammatory cytokine release and mediation of the acute phase protein response in fulminant hepatic failure.

Abstract

To study the relationship between interleukin-6 (IL-6), tumour necrosis factor (TNF) and the acute phase protein C-reactive protein (CRP) in patients with fulminant hepatic failure (FHF) and to investigate the potential of peripheral blood mononuclear cells (PBMC) isolated from these patients to stimulate CRP production by isolated human hepatocytes in vitro. Patients with FHF were studied at the time of their admission to the intensive care unit. Serum TNF and IL-6 were measured in 12 patients with FHF, PBMC from 6 of these patients were then cultured in the presence and absence of lipopolysaccharides (LPS). TNF and IL-6 in serum and supernatants were measured by ELISA. PBMC supernatants were added to isolated human hepatocytes and CRP production was measured. Serum IL-6 (348 +/- 172 pg/ml) and TNF (118.5 +/- 15.5 pg/ml) were elevated compared with healthy controls (not detected) and these observations were matched by elevated serum CRP in patients with FHF (38.9 +/- 7 mg/l). Both the production of IL-6 and TNF by PBMC isolated from patients with FHF and the potential of supernatants from these cells to stimulate CRP production by hepatocytes in vitro was significantly reduced compared with controls. Despite the observation that patients with FHF have an elevated hepatic acute phase response, PBMC from patients with FHF have reduced potential to produce IL-6 and TNF and elicit an acute phase response in vitro by the time of patient admission to the intensive care unit. One explanation for this observation is early activation and exhaustion of PBMC in vivo.