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 mi to gen-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-KB (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-B 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-B 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.
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Supported by SSAT Career Development Award 2001–2003 (M.M.) and by a VA Merit Award (J.N.).
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Murr, M.M., 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-κB. J Gastrointest Surg 7, 20–25 (2003). https://doi.org/10.1016/S1091-255X(02)00053-7
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DOI: https://doi.org/10.1016/S1091-255X(02)00053-7