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Regulation of Kupffer Cell TNF Gene Expression During Experimental Acute Pancreatitis, The Role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-κB
- Source :
- Journal of Gastrointestinal Surgery. 7:20-25
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
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-kappaB (NF-kappaB) in TNF gene expression within Kupffer cells. TNF and TNF-mRNA were measured in rat livers perfused with elastase. TNF, TNF-mRNA, NF-kappaB 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 (P0.03) and Kupffer cells (P0.001). Phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 and activated NF-kappaB were detected in Kupffer cells at 7 minutes; at 60 minutes, TNF-mRNA peaked and NF-kappaB returned to baseline, whereas all three kinases remained activated. Gadolinium inhibited elastase-induced upregulation of TNF-mRNA (P0.001), TNF production (P0.001), 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 (P0.001), but only UO126 inhibited activation of NF-kappaB. 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-kappaB. The seemingly limited duration of NF-kappaB activation may be important in "switching off" the cytokine cascade during acute pancreatitis.
- Subjects :
- Male
Transcriptional Activation
MAPK/ERK pathway
medicine.medical_specialty
Kupffer Cells
p38 mitogen-activated protein kinases
medicine.medical_treatment
Immunoblotting
Electrophoretic Mobility Shift Assay
Gadolinium
p38 Mitogen-Activated Protein Kinases
Rats, Sprague-Dawley
Downregulation and upregulation
Internal medicine
medicine
Animals
RNA, Messenger
Protein kinase A
Cells, Cultured
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Pancreatic Elastase
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
business.industry
Kinase
Kupffer cell
JNK Mitogen-Activated Protein Kinases
NF-kappa B
Gastroenterology
Rats
Up-Regulation
medicine.anatomical_structure
Cytokine
Endocrinology
Gene Expression Regulation
Pancreatitis
Acute Disease
Surgery
Tumor necrosis factor alpha
Mitogen-Activated Protein Kinases
business
Subjects
Details
- ISSN :
- 1091255X
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Journal of Gastrointestinal Surgery
- Accession number :
- edsair.doi.dedup.....ea461e28b031dbeeac0984572ddd6f2b