Dissociated glucocorticoids equipotently inhibit cytokine- and cAMP-induced matrix degrading proteases in rat mesangial cells
Dissociated glucocorticoids are synthetic ligands of the glucocorticoid receptor (GR) and which discriminate between transrepression and transactivation. These compounds were predicted to have large therapeutic benefits when compared to conventional glucocorticoids because of reduced side effects. I...
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| Veröffentlicht in: | Biochemical pharmacology 2005-08, Vol.70 (3), p.433-445 |
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| creator | Eberhardt, Wolfgang Kilz, Tobias Akool, El-Sayed Müller, Roswitha Pfeilschifter, Josef |
| description | Dissociated glucocorticoids are synthetic ligands of the glucocorticoid receptor (GR) and which discriminate between transrepression and transactivation. These compounds were predicted to have large therapeutic benefits when compared to conventional glucocorticoids because of reduced side effects. In this study, we compared the transrepressive properties of different dissociated glucocorticoids on the interleukin-1β (IL-1β)-activated metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA) expression in rat mesangial cells (MC). Both proteinases regulate the turnover of extracellular matrix (ECM). We demonstrate that the GR agonist RU 24858, equipotent to dexamethasone (DEX), exhibited strong suppressive effects on the IL-1β-induced MMP-9 and tPA mRNA levels concomitant with an inhibition of corresponding enzyme activities. In contrast, RU 24782 and RU 40066 exhibited weaker inhibitory activities on both proteinases. Mechanistically, the changes in MMP-9 expression level by different RUs were accompanied by an inhibition of cytokine-induced promoter activity indicating that the inhibition occurs on a transcriptional level. In parallel to the reduction in mRNA levels, we observed an attenuation of cytokine-induced DNA binding of nuclear factor kappa B (NF-κB) and reduced contents of the p65 subunit of NF-κB within cell nuclei. Along with these transrepressive activities RU 24858, RU 24782 and RU 40066 displayed similar transactivation potentials as indicated by induction of the glucocorticoid-inducible mouse mammary tumor virus (MMTV) reporter gene and by induced expression level of plasminogen activator inhibitor 1 (PAI-1). Interestingly, the different RUs affected the expression of cAMP-induced tPA and inducible NO synthase with the same potency as the IL-1β-induced protease expression thus indicating that these compounds equipotently modulate cytokine- and cAMP-driven gene expression. |
| doi_str_mv | 10.1016/j.bcp.2005.05.007 |
| format | Article |
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These compounds were predicted to have large therapeutic benefits when compared to conventional glucocorticoids because of reduced side effects. In this study, we compared the transrepressive properties of different dissociated glucocorticoids on the interleukin-1β (IL-1β)-activated metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA) expression in rat mesangial cells (MC). Both proteinases regulate the turnover of extracellular matrix (ECM). We demonstrate that the GR agonist RU 24858, equipotent to dexamethasone (DEX), exhibited strong suppressive effects on the IL-1β-induced MMP-9 and tPA mRNA levels concomitant with an inhibition of corresponding enzyme activities. In contrast, RU 24782 and RU 40066 exhibited weaker inhibitory activities on both proteinases. Mechanistically, the changes in MMP-9 expression level by different RUs were accompanied by an inhibition of cytokine-induced promoter activity indicating that the inhibition occurs on a transcriptional level. In parallel to the reduction in mRNA levels, we observed an attenuation of cytokine-induced DNA binding of nuclear factor kappa B (NF-κB) and reduced contents of the p65 subunit of NF-κB within cell nuclei. Along with these transrepressive activities RU 24858, RU 24782 and RU 40066 displayed similar transactivation potentials as indicated by induction of the glucocorticoid-inducible mouse mammary tumor virus (MMTV) reporter gene and by induced expression level of plasminogen activator inhibitor 1 (PAI-1). Interestingly, the different RUs affected the expression of cAMP-induced tPA and inducible NO synthase with the same potency as the IL-1β-induced protease expression thus indicating that these compounds equipotently modulate cytokine- and cAMP-driven gene expression.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2005.05.007</identifier><identifier>PMID: 15963473</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Cells, Cultured ; Cyclic AMP - antagonists & inhibitors ; Cyclic AMP - metabolism ; Cytokines - antagonists & inhibitors ; Cytokines - metabolism ; Dissociated glucocorticoids ; Extracellular matrix ; Extracellular Matrix - drug effects ; Extracellular Matrix - enzymology ; Glomerular Mesangium - cytology ; Glomerular Mesangium - drug effects ; Glomerular Mesangium - enzymology ; Glucocorticoids - chemistry ; Glucocorticoids - pharmacology ; Humans ; Matrix Metalloproteinase Inhibitors ; Matrix metalloproteinase-9 ; Matrix Metalloproteinases - metabolism ; Medical sciences ; Mouse mammary tumor virus ; Pharmacology. 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These compounds were predicted to have large therapeutic benefits when compared to conventional glucocorticoids because of reduced side effects. In this study, we compared the transrepressive properties of different dissociated glucocorticoids on the interleukin-1β (IL-1β)-activated metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA) expression in rat mesangial cells (MC). Both proteinases regulate the turnover of extracellular matrix (ECM). We demonstrate that the GR agonist RU 24858, equipotent to dexamethasone (DEX), exhibited strong suppressive effects on the IL-1β-induced MMP-9 and tPA mRNA levels concomitant with an inhibition of corresponding enzyme activities. In contrast, RU 24782 and RU 40066 exhibited weaker inhibitory activities on both proteinases. Mechanistically, the changes in MMP-9 expression level by different RUs were accompanied by an inhibition of cytokine-induced promoter activity indicating that the inhibition occurs on a transcriptional level. In parallel to the reduction in mRNA levels, we observed an attenuation of cytokine-induced DNA binding of nuclear factor kappa B (NF-κB) and reduced contents of the p65 subunit of NF-κB within cell nuclei. Along with these transrepressive activities RU 24858, RU 24782 and RU 40066 displayed similar transactivation potentials as indicated by induction of the glucocorticoid-inducible mouse mammary tumor virus (MMTV) reporter gene and by induced expression level of plasminogen activator inhibitor 1 (PAI-1). Interestingly, the different RUs affected the expression of cAMP-induced tPA and inducible NO synthase with the same potency as the IL-1β-induced protease expression thus indicating that these compounds equipotently modulate cytokine- and cAMP-driven gene expression.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cyclic AMP - antagonists & inhibitors</subject><subject>Cyclic AMP - metabolism</subject><subject>Cytokines - antagonists & inhibitors</subject><subject>Cytokines - metabolism</subject><subject>Dissociated glucocorticoids</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - drug effects</subject><subject>Extracellular Matrix - enzymology</subject><subject>Glomerular Mesangium - cytology</subject><subject>Glomerular Mesangium - drug effects</subject><subject>Glomerular Mesangium - enzymology</subject><subject>Glucocorticoids - chemistry</subject><subject>Glucocorticoids - pharmacology</subject><subject>Humans</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Matrix metalloproteinase-9</subject><subject>Matrix Metalloproteinases - metabolism</subject><subject>Medical sciences</subject><subject>Mouse mammary tumor virus</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Proteases</subject><subject>Rats</subject><subject>Tissue plasminogen activator</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhoMo7uzqD_Aiueitx6Q_kjSeltVVYUUPeg7VSfVYY3_MJmlxDv5308zA3hQKqgLPW7yVl7EXUmylkOrNftu5w7YUotmuJfQjtpFGV0XZKvOYbYQQKs9NecEuY9yvT6PkU3Yhm1ZVta427M87inF2BAk93w2Lm90cErmZfOR4v9BhTjil4chp-kEdJe6Oaf5JExYcJs_d9eevBU1-cVk_Qgr0m3vcBfA07fghZDVEjFnNAyQ-YoRpRzBwh8MQn7EnPQwRn5_7Fft--_7bzcfi7suHTzfXd4WrZZkK2ZcS8nkKURmQsvGdLkFrU4MWqmoqbJvO67oU3uheSFMaUL5ywtc1CC-qK_b6tDcbul8wJjtSXB3AhPMSrdJtq4X5PyhbI9u2rjMoT6ALc4wBe3sINEI4WinsGo7d2xyOXcOxawmdNS_Py5duRP-gOKeRgVdnAKKDoQ8wOYoPnGprkeHMvT1xmP_sF2Gw0RFOOQIK6JL1M_3Dxl8nBK3e</recordid><startdate>20050801</startdate><enddate>20050801</enddate><creator>Eberhardt, Wolfgang</creator><creator>Kilz, Tobias</creator><creator>Akool, El-Sayed</creator><creator>Müller, Roswitha</creator><creator>Pfeilschifter, Josef</creator><general>Elsevier Inc</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20050801</creationdate><title>Dissociated glucocorticoids equipotently inhibit cytokine- and cAMP-induced matrix degrading proteases in rat mesangial cells</title><author>Eberhardt, Wolfgang ; Kilz, Tobias ; Akool, El-Sayed ; Müller, Roswitha ; Pfeilschifter, Josef</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-1f21a0076ee68a115db72a7784a706353e95bd7420d87f01828a6d3c0d44a0d03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cyclic AMP - antagonists & inhibitors</topic><topic>Cyclic AMP - metabolism</topic><topic>Cytokines - antagonists & inhibitors</topic><topic>Cytokines - metabolism</topic><topic>Dissociated glucocorticoids</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix - drug effects</topic><topic>Extracellular Matrix - enzymology</topic><topic>Glomerular Mesangium - cytology</topic><topic>Glomerular Mesangium - drug effects</topic><topic>Glomerular Mesangium - enzymology</topic><topic>Glucocorticoids - chemistry</topic><topic>Glucocorticoids - pharmacology</topic><topic>Humans</topic><topic>Matrix Metalloproteinase Inhibitors</topic><topic>Matrix metalloproteinase-9</topic><topic>Matrix Metalloproteinases - metabolism</topic><topic>Medical sciences</topic><topic>Mouse mammary tumor virus</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Proteases</topic><topic>Rats</topic><topic>Tissue plasminogen activator</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Eberhardt, Wolfgang</creatorcontrib><creatorcontrib>Kilz, Tobias</creatorcontrib><creatorcontrib>Akool, El-Sayed</creatorcontrib><creatorcontrib>Müller, Roswitha</creatorcontrib><creatorcontrib>Pfeilschifter, Josef</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Eberhardt, Wolfgang</au><au>Kilz, Tobias</au><au>Akool, El-Sayed</au><au>Müller, Roswitha</au><au>Pfeilschifter, Josef</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dissociated glucocorticoids equipotently inhibit cytokine- and cAMP-induced matrix degrading proteases in rat mesangial cells</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2005-08-01</date><risdate>2005</risdate><volume>70</volume><issue>3</issue><spage>433</spage><epage>445</epage><pages>433-445</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>Dissociated glucocorticoids are synthetic ligands of the glucocorticoid receptor (GR) and which discriminate between transrepression and transactivation. These compounds were predicted to have large therapeutic benefits when compared to conventional glucocorticoids because of reduced side effects. In this study, we compared the transrepressive properties of different dissociated glucocorticoids on the interleukin-1β (IL-1β)-activated metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA) expression in rat mesangial cells (MC). Both proteinases regulate the turnover of extracellular matrix (ECM). We demonstrate that the GR agonist RU 24858, equipotent to dexamethasone (DEX), exhibited strong suppressive effects on the IL-1β-induced MMP-9 and tPA mRNA levels concomitant with an inhibition of corresponding enzyme activities. In contrast, RU 24782 and RU 40066 exhibited weaker inhibitory activities on both proteinases. Mechanistically, the changes in MMP-9 expression level by different RUs were accompanied by an inhibition of cytokine-induced promoter activity indicating that the inhibition occurs on a transcriptional level. In parallel to the reduction in mRNA levels, we observed an attenuation of cytokine-induced DNA binding of nuclear factor kappa B (NF-κB) and reduced contents of the p65 subunit of NF-κB within cell nuclei. Along with these transrepressive activities RU 24858, RU 24782 and RU 40066 displayed similar transactivation potentials as indicated by induction of the glucocorticoid-inducible mouse mammary tumor virus (MMTV) reporter gene and by induced expression level of plasminogen activator inhibitor 1 (PAI-1). Interestingly, the different RUs affected the expression of cAMP-induced tPA and inducible NO synthase with the same potency as the IL-1β-induced protease expression thus indicating that these compounds equipotently modulate cytokine- and cAMP-driven gene expression.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>15963473</pmid><doi>10.1016/j.bcp.2005.05.007</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Cells, Cultured Cyclic AMP - antagonists & inhibitors Cyclic AMP - metabolism Cytokines - antagonists & inhibitors Cytokines - metabolism Dissociated glucocorticoids Extracellular matrix Extracellular Matrix - drug effects Extracellular Matrix - enzymology Glomerular Mesangium - cytology Glomerular Mesangium - drug effects Glomerular Mesangium - enzymology Glucocorticoids - chemistry Glucocorticoids - pharmacology Humans Matrix Metalloproteinase Inhibitors Matrix metalloproteinase-9 Matrix Metalloproteinases - metabolism Medical sciences Mouse mammary tumor virus Pharmacology. Drug treatments Protease Inhibitors - pharmacology Proteases Rats Tissue plasminogen activator |
| title | Dissociated glucocorticoids equipotently inhibit cytokine- and cAMP-induced matrix degrading proteases in rat mesangial cells |
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