15-deoxy-Δ12,14-prostaglandin J2 Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-κB and MAPK Signaling in HepG2 Cells
15-Deoxy- -prostaglandin J2 (15d-PGJ2) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ2 regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25？ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ2 (2？μM and 5？μM) had no effect. Activin A and 15d-PGJ2 showed different regulatory effects on ActR and Smad expression, NF-κB p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ2 and activin, 15d-PGJ2 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-PGJ2 inhibited activin-induced NF-κB p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ2 suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-κB and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-κB and the MAPK pathway via interaction with 15d-PGJ2/activin/Smad signaling. 1. Introduction Activins are either heterodimers or homodimers of inhibin β subunits (βAβA, βBβB, or βAβB) [1]. The biological activities of activins are mediated by receptor complexes that consist of 2 different activin serine/threonine kinase receptors (ActR), type I (ActR I) and type II (ActR II) [2]. Smad2 and Smad3 proteins are phosphorylated by specific activated type I serine/threonine kinase receptors. Formation of dimeric complexes leads to phosphorylation of Smad2 and Smad3, subsequent complex formation with Smad4, and regulation of activin-responsive genes [3, 4]. Smad7 functions as an inhibitor of transforming growth factor-β (TGF-β) family signaling, including activin signaling [5, 6]. Activin-responsive genes have been implicated in the control of homeostasis, development, proliferation, apoptosis, differentiation, and inflammation in diverse cellular systems [2]. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a derivative of prostaglandin D2 and is a natural ligand of peroxisome proliferator-activated receptor-gamma (PPARγ), which is a transcriptional nuclear receptor [7, 8]. 15d-PGJ2 has a broad spectrum of
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