Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-kappa B

Liver injury is a manifestation of the systemic inflammatory response during acute pancreatitis. We have demonstrated that elastase induces macrophage tumor necrosis factor (TNF) production in distant organs, thus mimicking pancreatitis-associated organ injury. The aim of this study was to determine the mechanism by which elastase induces hepatic cytokine production. Rat livers (n=40) were perfused with elastase +/- gadolinium (Gd) to inhibit Kupffer cells. Liver parenchymal enzymes and TNF were measured in the effluent. In vitro, rat hepatocytes or Kupffer cells were treated with elastase (1 U/ml) +/- Gd (0.5 mg/ml) or pyrrolidine dithiocarbamate (PDTC; 0.5 mg/ml). TENT protein, TNF messenger RNA, and NF-kappaB activation were determined. In vivo, Gd blunted the elastase-induced TINT production and decreased AST, ALT, LDH, and nonviable cells (propidium iodide) (Pless than or equal to0.03 vs. elastase). In vitro, elastase induced TNF production from Kupffer cells (P<0.001 vs. control) but not from hepatocytes. Gd or PDTC significantly attenuated the elastase-induced TNF production (P<0.001). Elastase-induced overexpression of TNF messengerRNA and activation of NF-kappaB was attenuated by Gd. Pancreatic elastase induces a pattern of liver injury similar to that seen during acute pancreatitis by activating cytokine production and gene expression within Kupffer cells via NF-kappaB. Gd exhibits a protective effect against elastase-induced liver injury by inhibiting activation of NF-kappaB.