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Agonist‐specific regulation of monocyte chemoattractant protein‐1 expression by cyclooxygenase metabolites in hepatic stellate cells
Author(s) -
Efsen Eva,
Bonacchi Andrea,
Pastacaldi Sabrina,
Valente Anthony J.,
Wenzel Ulrich O.,
TostiGuerra Cristina,
Pinzani Massimo,
Laffi Giacomo,
Abboud Hanna E.,
Gentilini Paolo,
Marra Fabio
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.22761
Subject(s) - monocyte , hepatic stellate cell , cyclooxygenase , chemokine , cytokine , tumor necrosis factor alpha , chemistry , biology , endocrinology , pharmacology , medicine , inflammation , immunology , biochemistry , enzyme
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.