Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells

Fukuda, Yoshiaki; Sassa, Shigeru

doi:10.1016/0006-2952(94)90391-3

Cited by 58 publications

(11 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, OSM exposure of HepG2 cells resulted in a transcriptional repression of constitutive CYP1A1 expression (data not shown). Previously, it was reported that treatment of human hepatocytes and HepG2 cells with IL‐6‐type cytokines resulted in a decrease of basal as well as inducible expression of AHR‐dependent (CYP1A1, CYP1A2) and AHR‐independent (CYP3A4) CYP monooxygenases . The underlying molecular mechanisms are controversially discussed, but probably occur in a janus kinase/STAT‐independent manner .…”

Section: Discussionmentioning

confidence: 99%

The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells

Stobbe-Maicherski

Wolff

et al. 2013

FEBS J

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbons and related environmental pollutants. Besides drug metabolism, several studies have provided evidence that the AHR and its downstream targets trigger important developmental, physiological and pathophysiological processes. However, in contrast to the molecular mechanisms of AHR-dependent signaling pathways, the transcriptional regulation of the AHR gene itself is as yet only marginally understood. We found that the pleiotropic interleukin (IL)-6-type cytokine oncostatin M (OSM) is an inducer of AHR mRNA and protein expression in human HepG2 hepatocarcinoma cells. Analyses of the human AHR promoter revealed the existence of a putative signal transducer and activator of transcription (STAT)-binding element 5'-upstream of the transcription start site. By means of site-directed mutagenesis, inhibitor experiments and electrophoretic mobility shift assays, we demonstrated that this STAT motif is recognized by STAT3 to regulate basal and cytokine-inducible AHR expression in HepG2 cells. The identification of the AHR as a downstream target of IL-6-type cytokine-stimulated STAT3 signaling may contribute to a better understanding of the multiple facets of AHR during development, physiology and disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells

Stobbe-Maicherski

Wolff

et al. 2013

FEBS J

View full text Add to dashboard Cite

show abstract

“…There is evidence that both cis-genomic sequences within the 5Ј-promoter region of the CYP1A1 gene and trans-acting factors may play an important role in modulating basal and inducible expression (23)(24)(25)(26)(27). Moreover, several other factors also inhibit induction of CYP1A1 and/or CYP1A2 gene expression, and they include interleukin 6 in human HepG2 cells (28), transforming growth factor-␤ in human A549 lung cancer cells (29), interleukin-1␤, insulin, oxidative stress (e.g. H 2 O 2 ), epidermal growth factor, transforming growth factor-␣ in mouse or rat hepatocytes (30 -32), and the microtubule inhibitor nocodazole in mouse Hepa 1c1c7 cells (33).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Does Not Inhibit 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated Effects in MCF-7 and Hepa 1c1c7 Cells

Hoivik

Willett

Wilson

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)1 is an environmental contaminant that elicits a number of toxic and biochemical responses including chloracne, carcinogenesis, thymic atrophy and immune suppression, hypo/hyperplasia, hepatotoxicity, tumor promotion, reproductive and developmental toxicity, and induction of CYP isoenzymes and other drug-metabolizing enzymes (1). The aryl hydrocarbon receptor (AhR) has been identified as the initial cellular target for TCDD and related compounds, and results of most studies indicate that the effects of these chemicals are mediated through the AhR. The AhR is a ligand-induced nuclear transcription factor, which forms a heterodimer with the AhR nuclear translocator protein. Based on extensive studies with the CYP1A1 gene, ligand-induced transactivation is associated with interaction between the nuclear AhR complex and cis-genomic dioxin-responsive elements (DREs) located in the 5Ј-promoter region of responsive genes (2).Several studies have shown that TCDD modulates estrogen (E2)-induced pathways in human breast cancer cells. For example, treatment of MCF-7 cells with E2 increases cell proliferation (3); procathepsin D, cathepsin D (4), and pS2 (5) secretion; progesterone receptor (6) and HSP27 (7) and c-fos (8) gene expression; in cells cotreated with TCDD plus E2 all of the hormone-induced responses were decreased. The mechanism of AhR-mediated inhibition of E2-induced cathepsin D (9) and HSP27 (7) and pS2 (5) gene expression involves interactions of the nuclear AhR complex with inhibitory dioxin-responsive elements strategically located in the promoter regions of these genes.Vickers et al. (10) first pointed out that for a series of ERpositive and ER-negative breast cancer cell lines only the former cells were Ah-responsive as determined by induction of CYP1A1 gene expression by TCDD. In contrast, breast cancer cell lines such as ER-negative MDA-MB-231 (11) and Hs578T (12) cells express the AhR and AhR nuclear translocator proteins, but TCDD did not induce CYP1A1 or reporter gene activity in cells transiently transfected with Ah-responsive constructs. Research in this laboratory showed that transient transfection of the ER or variant ERs expressing activation function 1 or activation function 2 restored Ah responsiveness in MDA-MB-231 and Hs578T cells (11,12). Although the mechanisms of cross-talk between the ER and AhR are unknown the results suggest that the ER plays an important role in AhRmediated gene expression in both ER-positive and ER-negative human breast cancer cell lines. Surprisingly, Kharat and Saatcioglu (13) reported that E2 significantly inhibited TCDD-induced reporter gene activity in Hepa 1c1c7 cells transiently transfected with an Ah-responsive construct. Moreover, in gel mobility shift assays using nuclear extracts from cells treated with TCDD or TCDD plus E2 (cotreated), they reported that hormone treatment blocked formation of the TCDD-induced retarded band. These data were inconsistent with results of previous studies, and therefore the effects o...

show abstract

“…The effects of IL-6 on cytochrome P450 activity have been widely reported but are contrasting in nature. Earlier work using in vitro models has shown IL-6 to be capable of depressing the activity of a variety of cytochrome P450 isoforms (Williams, 1991;Fukuda et al, 1992;Fukuda and Sassa, 1994). However, the effects of IL-6 become less clear when administered in vivo because it has a variety of different effects depending on the isoform examined (Morgan, 1991;Morgan et al, 1994).…”

Section: Fig 4 the Effect Of Ifn-␥ On Cyp1a Activity In Astrocytesmentioning

confidence: 99%

The Role of Cytokines in the Depression of CYP1A Activity Using Cultured Astrocytes as an in Vitro Model of Inflammation in the Central Nervous System

Nicholson

Renton²

2002

Drug Metab Dispos

View full text Add to dashboard Cite

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The interaction and modulation of hepatic cytochrome P450 enzymes by infection and inflammation has been well described both in clinical settings and in animal models. Recent evidence found that inflammation in the central nervous system (CNS) leads to alterations in cytochrome P450 activity in both brain and liver. The bacterial endotoxin lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured astrocytes as a model of CNS inflammation. This inflammatory response involves a range of immune mediators, such as acute phase cytokines, nitric oxide, prostanoid products, and reactive oxygen species. It is hypothesized that cytokines, released during inflammation, act to modulate the expression of specific isoforms of cytochrome P450 resulting in altered activity levels. High levels of the cytokines tumor necrosis factor-␣ and interleukin-1␤ were released into culture medium after the addition of LPS to astrocyte cultures. When these same cytokines were added directly to the cultures, they also were able to modulate levels of CYP1A activity. The concurrent addition of dexamethasone to astrocytes blocked both the cytokine release and the alteration of CYP1A activity, thus supporting a role for these cytokines in this response. These results provide evidence suggesting an involvement of acute phase cytokines in mediating the LPS-induced depression of CYP1A activity in cultured astrocytes.

show abstract

Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells

Cited by 58 publications

References 40 publications

The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells

The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells

Estrogen Does Not Inhibit 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated Effects in MCF-7 and Hepa 1c1c7 Cells

The Role of Cytokines in the Depression of CYP1A Activity Using Cultured Astrocytes as an in Vitro Model of Inflammation in the Central Nervous System

Contact Info

Product

Resources

About