1. Regulation of Kupffer Cell TNF Gene Expression During Experimental Acute Pancreatitis: The Role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-κB
- Author
-
Murr, Michel M., Yang, Jun, Fier, Adam, Gallagher, Scott F., Carter, Gay, Gower Jr., William R., Norman, James G., and Gower, William R Jr
- Subjects
KUPFFER cells ,CELLULAR control mechanisms ,LIVER injuries ,PROTEIN kinases ,RNA metabolism ,ANIMAL experimentation ,BIOCHEMISTRY ,CELL culture ,CHEMICAL elements ,COMPARATIVE studies ,ELECTROPHORESIS ,GENES ,IMMUNOBLOTTING ,MACROPHAGES ,PHENOMENOLOGY ,RESEARCH methodology ,MEDICAL cooperation ,PANCREATITIS ,POLYMERASE chain reaction ,PROTEOLYTIC enzymes ,RATS ,RESEARCH ,TRANSFERASES ,TUMOR necrosis factors ,DNA-binding proteins ,EVALUATION research ,REVERSE transcriptase polymerase chain reaction ,ACUTE diseases - Abstract
We have demonstrated that Kupffer cell–derived tumor necrosis factor (TNF) mediates pancreatitis-associated liver injury. The aim of this study was to determine the role of p38 mitogen-activated protein kinase (MAPK), extracellular stress-related kinase 1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and nuclear factor–κB (NF-κB) in TNF gene expression within Kupffer cells. TNF and TNF-mRNA were measured in rat livers perfused with elastase. TNF, TNF-mRNA, NF-κB activation, and phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 were determined in Kupffer cells treated with elastase. Elastase increased TNF and upregulated TNF-mRNA in livers (P<0.03) and Kupffer cells (P<0.001). Phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 and activated NF-κB were detected in Kupffer cells at 7 minutes; at 60 minutes, TNF-mRNA peaked and NF-κB returned to baseline, whereas all three kinases remained activated. Gadolinium inhibited elastase-induced upregulation of TNF-mRNA (P < 0.001), TNF production (P<0.001), and attenuated SAPK/JNK, as well as ERK1/2, but not p38-MAPK. Both UO126 and SB203580 significantly inhibited elastase-induced upregulation of TNF-mRNA and TNF production (P<0.001), but only UO126 inhibited activation of NF-κB. It was concluded that pretranscriptional regulation of TNF gene expression in Kupffer cells follows an orderly activation of p38-MAPK, ERK1/2, and SAPK/JNK that may not converge on NF-κB. The seemingly limited duration of NF-κB activation may be important in “switching off” the cytokine cascade during acute pancreatitis. ( J Gastrointest Surg 2003;7:20–25.) [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF