Early up-regulation of chemokine expression in fulminant hepatic failure.
CC-chemokines recruit and activate macrophages and T lymphocytes, the major components of inflammatory infiltrates in fulminant hepatic failure (FHF). To analyse the role of CC-chemokines in the pathogenesis of FHF, this study examined serum levels and intrahepatic expression of MCP-1, MIP-1alpha, MIP-1beta, and RANTES in the livers and sera of patients with FHF and controls by ELISA, immunohistochemistry, and competitive RT-PCR. Serum levels and intrahepatic expression of all chemokines studied in FHF exceeded the levels in chronic liver diseases and normal controls. Distinct patterns of expression of each chemokine were noted on Kupffer cells, sinusoidal endothelial cells, hepatocytes, lymphocytes, and bile ducts. Intrahepatic chemokine expression correlated closely with the extent of infiltration by macrophages and T lymphocytes (r = 0.65-0.95, p < 0.001). The functional relationship between intrahepatic chemokine release and infiltration was confirmed in chemotaxis assays by inhibiting chemotaxis induced by homogenates of liver tissue obtained from FHF patients with neutralizing MCP-1, MIP-1alpha, MIP-1beta, and RANTES antibodies. The time course of CC-chemokine release was studied in the concanavalin A and the galactosamine/LPS mouse models of FHF. In both models, intrahepatic chemokine up-regulation occurred as an early event prior to hepatic infiltration and liver damage. The data indicate that an abundant intrahepatic release of CC-chemokines is an early and pivotal step in the pathogenesis of FHF.
Leifeld
Ludger
L
Department of Internal Medicine I, University of Bonn, Germany. l.leifeld@uni-bonn.de
Dumoulin
Franz-Ludwig
FL
Purr
Ingvill
I
Janberg
Katrin
K
Trautwein
Christian
C
Wolff
Martin
M
Manns
Michael Peter
MP
Sauerbruch
Tilman
T
Spengler
Ulrich
U
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000276:immunology; D017093:Liver Failure / Q000276:immunology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D008262:Macrophage Activation; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D019402:Macrophage Inflammatory Proteins; D008934:Mitogens; D012333:RNA, Messenger