TCDD-inducible plasminogen activator inhibitor type 2 (PAI-2) in human hepatocytes, HepG2 and monocytic U937 cells

Abstract

Induction of PAI-2 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been studied in human primary hepatocytes, hepatoma HepG2 cells and monocytic U937 cells, extending recent findings in human keratinocytes. PAI-2 represents a serpine-type protease inhibitor with wide-ranging implications in fibrinolysis, extracellular matrix proteolysis, growth factor activation and carcinogenesis. PAI-2 was induced by >10(-9) M TCDD in hepatocytes and HepG2 cells and by >10(-10) M TCDD in U937 cells. In the latter cell line, PAI-2 induction by TCDD and by 12-O-tetradecanoyl phorbol-13-acetate (TPA) has been compared. TCDD appeared to be less efficient than TPA as an inducer of PAI-2. In contrast to induction by TPA, PAI-2 induction by TCDD was found to be biphasic, with an early peak of mRNA at 1-3 h and a late peak at 12-24 h. A biphasic response was also seen at the protein level although production of PAI-2 protein lagged behind the corresponding mRNA. PAI-2 is known to contain AP-1 sites, i.e. Jun/Fos protein-binding sites, in its promotor region. Hence, PAI-2 induction by TCDD has originally been conceived to be due to an indirect response, secondary to the induction of Jun/Fos proteins. Therefore, expression of jun/fos genes and their AP-1 activity were studied at the early phase of PAI-2 induction by TCDD. TCDD did not increase mRNA of c-fos, c-jun, junB or junD (in contrast to TPA which markedly increased the expression of c-fos and junB), nor did TCDD increase AP-1 activity. In conclusion, the findings suggest that PAI-2 induction by TCDD is not restricted to human keratinocytes but includes liver cells and monocytic U937 cells. The induction mechanism is complex but the early phase does not appear to involve Jun/Fos proteins.

Levels of transforming growth factor β and transforming growth factor β receptors in rat liver during growth, regression by apoptosis and neoplasia

“…49 Further modulators of this complex cascade are hormones, cytokines, or xenobiotics, as the peroxisome proliferator gemfibrozil or the tumor promoter TCDD. [49][50][51][52] They may increase or decrease the local concentration of mature TGF-β 1 and may, thus, modulate autocrine/paracrine effects of this cytokine. An induced activation of TGF-β 1 may, therefore, be involved in the dramatic increase in apoptosis upon CPA-or NAF-withdrawal and in the high spontaneous apoptotic activity in HCC.…”

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation

“…At 70% confluency, cells were treated with either 10 nM TCDD (Cambridge Isotope Labs, Andover, MA) diluted in dimethyl sulfoxide (DMSO) or with an equivalent volume of DMSO alone (0.2% vol/vol). This concentration of TCDD has been shown to reproducibly elicit differential gene expression in human hepatoma cells, human liver adult stem cells, and primary hepatocytes from human, mouse, and rat (Dere et al 2011; Forgacs et al 2013; Gohl et al 1996; Kim et al 2009). The 10 nM concentration of TCDD is not overtly toxic to primary hepatocytes (Black et al 2012) and is about 10-fold less than the hepatic TCDD concentration in rats 7 days after a single subcutaneous dose of 3 μg/kg TCDD (Abraham et al 1988).…”

Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis

“…This effect has been observed in multiple liver cell types [Puga et al, 1992;Enan et al, 1998b;Ashida et al, 2000], but not in all [Gohl et al, 1996]. In other cells, such as LPS-activated B cells, TCDD downregulates AP-1 expression [Suh et al, 2002], suggesting a cell type-dependent effect of AHR ligands on immediate-early protooncogene induction.…”