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Agonist-specific regulation of monocyte chemoattractant protein-1 expression by cyclooxygenase metabolites in hepatic stellate cells.
Efsen, E; Bonacchi, A; Pastacaldi, S; Valente, A J; Wenzel, U O; Tosti-Guerra, C; Pinzani, M; Laffi, G; Abboud, H E; Gentilini, P; Marra, F.
Afiliação
  • Efsen E; Dipartimento di Medicina Interna, University of Florence, Italy.
Hepatology ; 33(3): 713-21, 2001 Mar.
Article em En | MEDLINE | ID: mdl-11230753
ABSTRACT
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 alpha (TNF-alpha) or interleukin-1alpha (IL-1alpha). 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-gamma) 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-alpha and IL-1alpha markedly increased the expression of COX-2, IFN-gamma 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-kappaB (NF-kappaB) inhibitor, demonstrating that prostaglandins modulate MCP-1 expression via production of cAMP. On the other hand, the action of NF-kappaB inhibitors was negligible in IFN-gamma-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.
Assuntos
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Base de dados: MEDLINE Assunto principal: Prostaglandina-Endoperóxido Sintases / Quimiocina CCL2 / Fígado Idioma: En Ano de publicação: 2001 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Prostaglandina-Endoperóxido Sintases / Quimiocina CCL2 / Fígado Idioma: En Ano de publicação: 2001 Tipo de documento: Article