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
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Murr, Michel M., Yang, Jun, Fier, Adam, Gallagher, Scott F., Carter, Gay, Gower Jr., William R., Norman, James G., and Gower, William R Jr
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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
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