Abstract
Peroxizome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor family of transcription factors that regulate adipocyte differentiation. Recent studies indicate that liganded PPAR not only promotes differentiation but also inhibits the activation of macrophages. Osteopontin, a component of extracellular matrix, is synthesized by macrophages in atherosclerotic plaques. In this study, we examined whether PPAR ligand regulates osteopontin gene expression in THP-1 cells, a cell line derived from human monocytic leukemia cells which can differentiate to macrophage upon stimulation with phorbol ester PMA. Northern blot analysis showed that osteopontin expression is markedly induced in response to PMA. Troglitazone, a PPAR ligand, dramatically attenuated the PMA-induced osteopontin expression. Transient transfection assays of the human osteopontin promoter/luciferase construct which contains a 5'-flanking region between -1500 and +87 relative to the transcription start site demonstrate that either treatment with troglitazone or cotransfection of PPARγ expression vector inhibits osteopontin promoter activity. These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through PPARγ activation, and suggest the role of troglitazone in inhibiting the ability of macrophages to produce extracellular matrix, which is particularly relevant to atherosclerotic plaque formation.
