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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-kappaB.
J Gastrointest Surg. 2003 Jan; 7(1):20-5.JG

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 (P<0.03) and Kupffer cells (P<0.001). 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 (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-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.

Authors+Show Affiliations

Department of Surgery, James A Haley VA Hospital, University of South Florida, Tampa, Florida, USA. mmurr@hsc.us.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

12559181

Citation

Murr, Michel M., et al. "Regulation of Kupffer Cell TNF Gene Expression During Experimental Acute Pancreatitis: the Role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB." Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract, vol. 7, no. 1, 2003, pp. 20-5.
Murr MM, Yang J, Fier A, et al. Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB. J Gastrointest Surg. 2003;7(1):20-5.
Murr, M. M., Yang, J., Fier, A., Gallagher, S. F., Carter, G., Gower, W. R., & Norman, J. G. (2003). Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB. Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract, 7(1), 20-5.
Murr MM, et al. Regulation of Kupffer Cell TNF Gene Expression During Experimental Acute Pancreatitis: the Role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB. J Gastrointest Surg. 2003;7(1):20-5. PubMed PMID: 12559181.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK/JNK, and NF-kappaB. AU - Murr,Michel M, AU - Yang,Jun, AU - Fier,Adam, AU - Gallagher,Scott F, AU - Carter,Gay, AU - Gower,William R,Jr AU - Norman,James G, PY - 2003/2/1/pubmed PY - 2003/4/23/medline PY - 2003/2/1/entrez SP - 20 EP - 5 JF - Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract JO - J Gastrointest Surg VL - 7 IS - 1 N2 - 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 (P<0.03) and Kupffer cells (P<0.001). 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 (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-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. SN - 1091-255X UR - https://www.unboundmedicine.com/medline/citation/12559181/Regulation_of_Kupffer_cell_TNF_gene_expression_during_experimental_acute_pancreatitis:_the_role_of_p38_MAPK_ERK1/2_SAPK/JNK_and_NF_kappaB_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1091255X02000537 DB - PRIME DP - Unbound Medicine ER -