TY - JOUR
T1 - Agonist-specific regulation of monocyte chemoattractant protein-1 expression by cyclooxygenase metabolites in hepatic stellate cells
AU - Efsen, Eva
AU - Bonacchi, Andrea
AU - Pastacaldi, Sabrina
AU - Valente, Anthony J.
AU - Wenzel, Ulrich O.
AU - Tosti-Guerra, Cristina
AU - Pinzani, Massimo
AU - Laffi, Giacomo
AU - Abboud, Hanna E.
AU - Gentilini, Paolo
AU - Marra, Fabio
N1 - Funding Information:
Abbreviations: HSC, hepatic stellate cells; MCP-1, monocyte chemoattractant protein-1; COX, cyclooxygenase; IL-1α, interleukin-1α; TNF-α, tumor necrosis factor α; IFN-g, interferon gamma; cAMP, cyclic adenosine monophosphate; NF-kB, nuclear factor-kB; PGE2, prostaglandin E2. From the 1Dipartimento di Medicina Interna, University of Florence, Italy; 2Department of Medicine, University of Texas Health Science Center, San Antonio, TX; and 3Division of Nephrology, University of Hamburg, Germany. Received May 19, 2000; accepted December 23, 2000. Supported by grants from MURST (Project: Molecular and cellular biology of liver fibrosis) and by the Italian Liver Foundation. E.E. was supported in part by the Tode’s Travel Grant and by the Rektorkollegiets Kulturaftalestipendium. Address reprint requests to: Fabio Marra, M.D., Dipartimento di Medicina Interna, University of Florence, Viale Morgagni, 85,I-50134 Florence, Italy. E-mail: f.marra@dfc.unifi.it; fax: 39-055-417-123. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3303-0029$35.00/0 doi:10.1053/jhep.2001.22761
PY - 2001
Y1 - 2001
N2 - Activated hepatic stellate cells (HSC) regulate the liver "wound-healing" response through expression of chemokines, including monocyte chemoattractant protein-1 (MCP-1), which participate in the formation of the inflammatory infiltrate during liver injury. Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins, which may contribute to the inflammatory response. In this study, we investigated the effects of COX inhibitors on the expression of MCP-1 in cultured HSC. Pretreatment of HSC with nonspecific COX inhibitors such as indomethacin or ibuprofen markedly reduced the expression of MCP-1 caused by exposure to tumor necrosis factor α (TNF-α) or interleukin-1α (IL-1α). NS-398, a specific COX-2 inhibitor, also resulted in a dose-dependent inhibition of MCP-1 gene and protein expression. These effects were dependent on reduced MCP-1 transcription, as established using a reporter plasmid. In contrast, the up-regulation of MCP-1 expression caused by interferon gamma (IFN-γ) was not sensitive to COX inhibitors. Quiescent HSC did not show detectable expression of COX-2, which became evident after activation in culture, and while TNF-α and IL-1α markedly increased the expression of COX-2, IFN-γ did not have any effects. Pretreatment of HSC with the stable cyclic adenosine monophosphate (cAMP) analog, 8-bromo cAMP, reverted the effects of the COX-2 inhibitor, but not of a nuclear factor-κB (NF-κB) inhibitor, demonstrating that prostaglandins modulate MCP-1 expression via production of cAMP. On the other hand, the action of NF-κB inhibitors was negligible in IFN-γ-stimulated cells. These findings indicate that cross-talk between cytokines and a prostaglandin-cAMP pathway differentially regulates the proinflammatory potential of HSC, contributing to the modulation of liver tissue inflammation.
AB - Activated hepatic stellate cells (HSC) regulate the liver "wound-healing" response through expression of chemokines, including monocyte chemoattractant protein-1 (MCP-1), which participate in the formation of the inflammatory infiltrate during liver injury. Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins, which may contribute to the inflammatory response. In this study, we investigated the effects of COX inhibitors on the expression of MCP-1 in cultured HSC. Pretreatment of HSC with nonspecific COX inhibitors such as indomethacin or ibuprofen markedly reduced the expression of MCP-1 caused by exposure to tumor necrosis factor α (TNF-α) or interleukin-1α (IL-1α). NS-398, a specific COX-2 inhibitor, also resulted in a dose-dependent inhibition of MCP-1 gene and protein expression. These effects were dependent on reduced MCP-1 transcription, as established using a reporter plasmid. In contrast, the up-regulation of MCP-1 expression caused by interferon gamma (IFN-γ) was not sensitive to COX inhibitors. Quiescent HSC did not show detectable expression of COX-2, which became evident after activation in culture, and while TNF-α and IL-1α markedly increased the expression of COX-2, IFN-γ did not have any effects. Pretreatment of HSC with the stable cyclic adenosine monophosphate (cAMP) analog, 8-bromo cAMP, reverted the effects of the COX-2 inhibitor, but not of a nuclear factor-κB (NF-κB) inhibitor, demonstrating that prostaglandins modulate MCP-1 expression via production of cAMP. On the other hand, the action of NF-κB inhibitors was negligible in IFN-γ-stimulated cells. These findings indicate that cross-talk between cytokines and a prostaglandin-cAMP pathway differentially regulates the proinflammatory potential of HSC, contributing to the modulation of liver tissue inflammation.
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U2 - 10.1053/jhep.2001.22761
DO - 10.1053/jhep.2001.22761
M3 - Article
C2 - 11230753
AN - SCOPUS:17744398428
VL - 33
SP - 713
EP - 721
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -