15-Deoxy-Delta(12,14)-Prostaglandin J(2) Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-kappa B and MAPK Signaling in HepG2 Cells

Abstract

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ(2) regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ(2) (2 mu M and 5 mu M) had no effect. Activin A and 15d-PGJ(2) showed different regulatory effects on ActR and Smad expression, NF-kappa B p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ(2) and activin, 15d-PGJ(2) inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ(2) inhibited activin-induced NF-kappa B p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ(2) suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-kappa B and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-kappa B and the MAPK pathway via interaction with 15d-PGJ(2)/activin/Smad signaling.