Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone

Jonat, Carsten; Rahmsdorf, Hans J.; Park, Kun-Koo; Cato, Andrew C. B.; Gebel, Stephan; Ponta, Helmut; Herrlich, Peter

doi:10.1016/0092-8674(90)90395-u

Cited by 1,524 publications

(876 citation statements)

References 84 publications

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“…In fact, the down-modulation of the transactivating function of AP-1 by GR was suggested to be mediated through the interaction with either the preexisting unbound or DNA-bound AP-1. This suggestion was supported by coprecipitation experiments with AP-1 and GR (Jonat et al, 1990).…”

Section: Introductionmentioning

confidence: 69%

“…Glucocorticoid hormones have been reported to be potent inhibitors of MMP-1 and MMP-3 of which expression can be induced by AP-1 stimulated by phorbol esters such as TPA (Jonat et al, 1990;Nicolson et al, 1990;SchuÈ le et al, 1990). It has been also reported that the repression of AP-1-responsive genes which is located in a TPA responsible element (TRE) is mediated by glucocorticoid receptor (GR) through a direct interaction with c-Jun (Diamond et al, 1990;Lucibello et al, 1990;SchuÈ le et al, 1990;Touray et al, 1991;Yang-Yen et al, 1990) or c-Fos (Kerppola et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

et al. 1998

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We have previously reported that ursolic acid, a pentacyclic triterpene acid, inhibited the invasion of HT1080 human ®brosarcoma cells by reducing the expression of matrix metalloproteinase-9. Since the chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid, we investigated whether ursolic acid acts through the glucocorticoid receptor. The expression of matrix metalloproteinase-9 is thought to be regulated similarly with matrix metalloproteinase-1 and matrix metalloproteinase-3 as containing common 2-O-tetradecanoylphorbol-acetate responsible region, where AP-1 proteins can bind. Dexamethasone has been studied to repress the 2-O-tetradecanoylphorbolacetate-induced expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 through a glucocorticoid receptor-mediated manner. In Northern blot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 induced by 2-O-tetradecanoylphorbol-acetate. Similarly, ursolic acid down-regulated 2-O-tetradecanoylphorbolacetate-induction of matrix metalloproteinase-9 gene in the same manner of dexamethasone. RU486, a potent glucocorticoid receptor antagonist, was used for identifying that ursolic acid-induced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor. The e ect of ursolic acid on the matrix metalloproteinase-9 expression was blocked by RU486, suggesting that ursolic acid acts via a glucocorticoid receptor in the regulation of matrix metalloproteinase-9. Western blot analysis and immunocytochemistry showed that ursolic acid increased glucocorticoid receptor fraction in the nucleus, although it decreased the synthesis of glucocorticoid receptor mRNA. In addition, ursolic acid did not decrease the expression of c-jun and DNAbinding activity of AP-1 to its cognate sequences. Taken together, we suggest that ursolic acid may induce the repression of matrix metalloproteinase-9 by stimulating the nuclear translocation of glucocorticoid receptor, and the translocated glucocorticoid receptor probably downmodulating the trans-activating function of AP-1 to 2-Otetradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

et al. 1998

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“…Dexamethasone, a potent immunosuppressive agent, inhibited both the gene expression and protein secretion by thyrocytes as has been shown in other cell types [32]. The inhibition of gene expression by glucocorticoids is generally caused through an interaction with glucocorticoid-responsive elements in the promoter regions of genes, a modulation of AP-1 DNA binding activity [33] or/ and through production of I~cB, an inhibitory molecule for nuclear factor kappa B (NF-nB) [34,35]. Accordingly, these mechanism(s) may probably operate in thyrocytes.…”

Section: Discussionmentioning

confidence: 99%

Expression of monocyte chemoattractant protein‐1 mRNA and protein in cultured human thyrocytes

et al. 1996

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Monocytes as well as lymphocytes infiltrate in the stroma of thyroid tissue in autoimmune and destructive thyroiditis. Monocyte chemoattractant protein-1 (MCP-I) is a cytokine that attracts T-lymphocytes as well as monocytes. Using human thyrocytes in primary cultures, we show that expression of MCP-1 mRNA and protein is remarkably stimulated by both interleukin-1 (IL-1) and tumor necrosis factor-~ (TNF-ct), and also that interferon-T (IFN-~/) by itself is a weak stimulant but has a synergistic activity with either IL-1 or TNF-c¢, The finding indicates that MCP-1 can be produced by thyrocytes themselves, suggesting a possible role of thyrocytes on accumulation of monocytes and T-lymphocytes to the tissue from the blood in autoimmune and destructive thyroiditis.

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“…Activation of AP-1 induces the transcription of several pro-inflammatory genes, including that of the metalloproteinases MMP-2 and MMP-9. These MMPs hydrolyze extracellular matrix proteins such as collagen, which normally function to localize inflammatory reactions within tissues [8,9,10]. Suppression of AP-1 activity by GC reduces expression of MMP-2 and MMP-9 and, thus, may limit the extent of inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…After secretion, ADAMTS enzymes undergo processing, including cleavage of the N-terminal signal peptide and pro-domain and of the C-terminal region, which affects substrate specificity and localization of the enzymes [12]. Their known functions include collagen processing (ADAMTS2, 3,14), cleavage of matrix proteoglycans (ADAMTS4, 5), inhibition of angiogenesis (ADAMTS1, 8), and blood coagulation homoeostasis (ADAMTS13) [11].…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

et al. 2007

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The regulated expression of ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs), a secreted metalloproteinase involved in the processing of procollagen to collagen, was studied in peripheral blood mononuclear cells (PBMC). Stimulation with glucocorticoids (GC) resulted in a pronounced dose-and timedependent increase of ADAMTS2 mRNA levels in PBMC. The increase of ADAMTS2 expression was specific for CD14++ monocytes (440-fold) and alveolar macrophages (200-fold), whereas CD3+ (T lymphocytes), phytohemagglutinin-activated CD3+ (T lymphocytes), and CD19+ (B lymphocytes) showed no significant changes in ADAMTS2 mRNA after GC treatment. Treatment of monocyte-derived macrophages (MDM) with GC also resulted in an increase of ADAMTS2 protein in the culture tissue media. Using the GC analog RU486, GC-mediated induction of ADAMTS2 mRNA was blocked, implicating that GC acts specifically via the GCreceptor. In agreement with findings in blood monocytes, cell lines of the monocytic lineage (MM6, THP-1) showed significant GC-induced significant increases in ADAMTS2 mRNA, while in epithelial cells (A549, Calu-3, Colo320, BT-20) and fibroblast (MRC-5, WI-38, and two NHDF-c cell types from adult cheek and upper arm), they showed no or little responsiveness to GC. As macrophages have important functions in immune defense and tissue homeostasis, these findings suggest that GC-mediated specific induction of ADAMTS2 in these cells may play a crucial role in the resolution of inflammation and wound repair.

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Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone

Cited by 1,524 publications

References 84 publications

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

Expression of monocyte chemoattractant protein‐1 mRNA and protein in cultured human thyrocytes

Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids

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