Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Hy, Oh; Namkoong, Seung; Sj, Lee; Por, Elaine D.; Ck, Kim; Tr, Billiar; Ja, Han; Ks, Ha; Ht, Chung; Yg, Kwon; H, Lee; Kim, Yong-Mi

doi:10.1038/sj.cdd.4401771

Cited by 52 publications

(34 citation statements)

References 45 publications

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“…In contrast, the extrinsic or death receptor pathway can bypass mitochondrial signaling through direct activation of caspase 3 by caspase 8 13,15 thus it is not surprising that increased levels of Bcl-x L would not provide significant protection in this scenario. Interestingly, our results differ from Oh et al 35 who recently reported that primary hepatocytes could be protected from Fas ligand induced apoptosis by large doses of dexamethasone (5 mM) via upregulation of cFLIP. We attempted to reproduce their results in our hepatoma cells, however, we found no antiapoptotic effects of Dex either with physiological doses (Figure 2) or the higher dose used by Oh et al (data not shown).…”

Section: Discussioncontrasting

confidence: 57%

Glucocorticoids inhibit the apoptotic actions of UV-C but not Fas ligand in hepatoma cells: direct evidence for a critical role of Bcl-xL

2006

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Our laboratory has shown that glucocorticoids can inhibit apoptosis in rat hepatoma cells; however, the mechanisms are incompletely understood. To address this issue we sought to determine if glucocorticoid inhibition is effective when death is induced by stimuli that more selectively activate either the intrinsic (UV-C) or extrinsic (FasL) apoptotic pathways. Using flow cytometric analysis, we show that pretreatment of HTC cells with dexamethasone (Dex) inhibits UV-C-but not FasL-induced apoptosis. This inhibition requires Dex pretreatment and can be abrogated by the glucocorticoid antagonist RU486 indicating glucocorticoid receptor-mediated action. Dex increases anti-apoptotic Bcl-x L at both mRNA and protein levels. The Bcl-x L protein level remains elevated even after apoptosis induction with either UV-C or FasL although only UV-C-induced cell death is inhibited. Repression of Bcl-x L protein with siRNA abrogates the anti-apoptotic effect of glucocorticoids. Together these data provide direct evidence that Bcl-x L mediates glucocorticoid inhibition of UV-C induced apoptosis.

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Section: Discussioncontrasting

confidence: 57%

Glucocorticoids inhibit the apoptotic actions of UV-C but not Fas ligand in hepatoma cells: direct evidence for a critical role of Bcl-xL

2006

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“…Immunoblots were analyzed by scanning densitometry for ErbB2 (left) and ERK1/2 (right) at 72 h. Note that 10 Ϫ6 M dexamethasone diminishes ErbB2 and ERK1/2 expression. spontaneous apoptosis through the induction of Bcl-2 and Bcl-xL (4), and they also inhibit the TNF and Fas death receptor-mediated apoptosis through the upregulation of Flice inhibitory protein (cFlip) (29). Some investigators have reported that dexamethasone increases EGF-stimulated DNA synthesis (26,30), but others have reported that dexamethasone inhibits it (34,35).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes

Scheving

Buchanan²,

Krause³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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WE. Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes. Am J Physiol Gastrointest Liver Physiol 293: G552-G559, 2007. First published June 21, 2007; doi:10.1152/ajpgi.00140.2007.-Glucocorticoids paradoxically exert both stimulatory and inhibitory effects on the proliferation of cultured rat hepatocytes. We studied the effects of dexamethasone, a synthetic glucocorticoid, on the proliferation of cultured rat hepatocytes. The timing of growth factor addition modified the action of high-dose dexamethasone (10 Ϫ6 M) on DNA synthesis. When we added transforming growth factor-␣ at the time of plating, 10 Ϫ6 M dexamethasone weakly stimulated DNA synthesis by 26% relative to cells cultured in dexamethasone-free media. When we delayed growth factor addition until 24 -48 h after plating, 10 Ϫ6 M dexamethasone inhibited DNA synthesis by 50%. Using immunological methods, we analyzed the expression and signaling patterns of the ErbB kinases in dexamethasone-treated cells. High-dose dexamethasone stabilized the expression of epidermal growth factor receptor (EGFr) and ErbB3, and it suppressed the de novo expression of ErbB2 that occurs during the third and fourth day of culture in 10 Ϫ8 M dexamethasone. High-dose dexamethasone by 72 h suppressed basal and EGF-associated phosphorylation of ERK and Akt. The reduction in ERK1/2 phosphorylation correlated with suppression of a culture-dependent increase in Son-of sevenless 1 (Sos1) and ERK1/2 expression. Highdose dexamethasone in hepatocytes stabilized or upregulated several inhibitory effectors of EGFr/ErbB2 and ERK, including receptorassociated late transducer (RALT) and MKP-1, respectively. Thus 10 Ϫ6 M dexamethasone exerts a time-dependent and redundant inhibitory effect on EGFr-mediated proliferative signaling in hepatocytes, targeting not only the ErbB proteins but also their various positive and negative effectors.liver; EGF; TGF-␣; cell culture DEXAMETHASONE, A SYNTHETIC glucocorticoid, is frequently included in the medium of cultured hepatocytes to improve their survival and function. In most experimental models, dexamethasone inhibits hepatocyte growth in vivo. For example, when injected into the rat, dexamethasone inhibits the striking increase in hepatocyte proliferation that occurs after 70% hepatectomy (28) or in transplanted livers following cold preservation and reperfusion (13). Likewise, dexamethasone has been reported to inhibit the proliferation of rat hepatocytes (34,35) and liver-derived cell lines (24). In primary hepatocyte culture, however, other investigators have reported that dexamethasone enhances epidermal growth factor (EGF)-stimulated DNA synthesis (26, 30). We hypothesized that these divergent observations result from differential effects of dexamethasone on one or more components of EGF receptor signaling.Fetal hepatocytes express three of the four ErbB tyrosine kinase receptors (EGFr, ErbB2, and ErbB3), but by 3 wk of age, ErbB2 is largely extinguished (10)...

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“…Various anti-apoptotic modalities ameliorate renal dysfunction secondary to renal IRI. 11 GCs have antiapoptotic effects on other cell lines [12][13][14] ; however, it is unknown whether GCs have such effects on the proximal tubular cell, the cell that is most vulnerable to renal IRI. Moreover, the renal proximal tubular epithelial cells are "steroid insensitive" with respect to its direct anti-inflammatory effects.…”

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confidence: 99%

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

Kumar¹,

Allen²,

Kieswich³

et al. 2009

Journal of the American Society of Nephrology

109

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In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemiareperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.

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Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Cited by 52 publications

References 45 publications

Glucocorticoids inhibit the apoptotic actions of UV-C but not Fas ligand in hepatoma cells: direct evidence for a critical role of Bcl-xL

Glucocorticoids inhibit the apoptotic actions of UV-C but not Fas ligand in hepatoma cells: direct evidence for a critical role of Bcl-xL

Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

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