Early up‐regulation of chemokine expression in fulminant hepatic failure

Abstract

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.

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment

“…Early up-regulation of CC-chemokines such as MCP-1, macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-1␤, and RANTES, have been demonstrated in mouse models of fulminant hepatic failure including concanavalin A and galactosamine/lipopolysaccharide, with expression occurring prior to hepatic inflammatory cell infiltration and liver damage. 32 The observations in CFLD and BA liver, serum, and bile are supported by experiments using the BDL rat model. Hsieh and colleagues have previously shown increased MCP-1 expression in BDL rats treated with Roux-en-Y choledochojejunostomy and E. coli-induced cholangitis.…”

CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis

“…[12][13][14][15] Specifically, intravenous administration of con A in mice mimics FH in humans in the following ways: (1) systemic immune activation and recruitment of activated T cells to the liver and stimulation of hepatic antigen-presenting cells (APCs) (i.e., Kupffer cells); 12,16,17 (2) acute dose-dependent liver injury, which ranges in spectrum from mild hepatitis to liver failure; 2,3 (3) hepatocyte death mainly due to apoptosis and driven by both FasL/Fas and tumor necrosis factor ␣ (TNF-␣) pathways; [18][19][20] (4) a pivotal role of the cytokines TNF-␣ and interferon ␥ (IFN-␥) in the development of hepatitis; 14,21,22 and (5) upregulation of hepatic C-C chemokine expression. 23,24 Therefore, given the central role played by CD154 -CD40 interactions in regulating the cellular immune response and the observation of an upregulation of CD40 expression and infiltration of CD154-expressing lymphocytes in the livers of patients with FH, we investigated the potential role of CD154 in the development of con A-induced hepatitis.…”

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…MDSCs may also serve as negative feedback during liver inflammation and their dysfunction could contribute to liver pathology [27,28]. Monocyte migration into the liver is facilitated by the production of CCL2, which is released in the first 1-4 h after the onset of CCl 4 -induced liver injury [21,29,30]. IL-1α can promote CCL2, as well as CCL3, CCL4, CCL5, CXCL2 productions [31,32].…”