Hepatocyte Transplantation-Induced Liver Inflammation Is Driven by Cytokines-Chemokines Associated With Neutrophils and Kupffer Cells

Department of Medicine, Marion Bessin Liver Research Center, Diabetes Research Center and Cancer Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Gastroenterology (Impact Factor: 16.72). 05/2009; 136(5):1806-17. DOI: 10.1053/j.gastro.2009.01.063
Source: PubMed


Hepatocyte transplantation-induced liver inflammation impairs cell engraftment. We defined whether proinflammatory cytokines and chemokines played roles in regulation of hepatocyte engraftment in the liver.
We performed studies over up to 3 weeks in rat hepatocyte transplantation systems. Expression of 84 cytokine-chemokine genes was studied by quantitative real-time polymerase chain reactions. Expression of selected up-regulated genes was verified by immunohistochemistry. Hepatic recruitment of neutrophils was demonstrated by myeloperoxidase activity assays, and Kupffer cell activation was established by carbon phagocytosis assays. The role of neutrophils and Kupffer cells in regulating expression of cytokine-chemokine genes as well as cell engraftment was determined by cell depletion studies.
Within 6 hours after syngeneic cell transplantation, expression of 25 cytokine-chemokine genes increased by 2- to 123-fold, P < .05. These genes were largely associated with activated neutrophils and macrophages, including chemokine ligands, CXCL1, CXCL2, CCL3, CCL4; chemokine receptors, CXCR1 or CXCR2, CCR1, CCR2; and regulatory cytokines tumor necrosis factor alpha and interleukin-6. Inflammatory cells in the liver immunostained for CCR1, CCR2, CXCR1, and CXCR2, which indicated that up-regulated messenger RNA was appropriately translated. When neutrophils and Kupffer cells were depleted with neutrophil antiserum and gadolinium chloride, respectively, before transplanting cells, cell transplantation-induced cytokine-chemokine responses were attenuated. Virtually all abnormalities subsided in animals treated with neutrophil antiserum plus gadolinium chloride. Moreover, depletion of neutrophils or Kupffer cells improved engraftment of transplanted cells.
Cell transplantation-induced liver inflammation involves proinflammatory cytokine-chemokine systems capable of modulation by neutrophils and Kupffer cells. This offers new directions for optimizing cell therapy strategies.

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    • "In recent years, novel targets have been defined to improve engraftment of transplanted cells at these stages and several drug-based strategies have been developed in preclinical models that are potentially clinically relevant for enhancing cell engraftment in the liver (Table 3). The major concepts have concerned use of drugs to treat subjects prior to cell transplantation, such that vascular or inflammatory changes induced by cell transplantation are abolished or minimized, the endothelial barrier interposed between liver sinusoids and parenchyma is disrupted, or hepatic stellate cells are induced to release beneficial substances , e.g., VEGF [58] [59] [62] [63]. Similarly, novel concepts have been developed in rodents where donor cells may be modified prior to transplantation, e.g., by addition of extracellular matrix components for better endothelial adhesion or incubation with drugs to block endothelin (ET)-1 receptors, which otherwise may transduce deleterious intracellular signals to activate NF-jB-mediated cell death [63] [64]. "
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    • "The only resident liver cells to express CCR2 are Kupffer cells and hepatic stellate cells (Friedman, 2008b; Krohn et al., 2009). As noted previously, Kupffer cells are an important source of CCL2 whose production is stimulated by ROS. "
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