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. In this study, we compared the transrepressive properties of different dissociated glucocorticoids on the interleukin-1beta (IL-1beta)-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-1beta-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-kappaB) and reduced contents of the p65 subunit of NF-kappaB 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-1beta-induced protease expression thus indicating that these compounds equipotently modulate cytokine- and cAMP-driven gene expression.
Eberhardt
Wolfgang
W
Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. w.eberhardt@em.uni-frankfurt.de
Kilz
Tobias
T
Akool
El-Sayed
el-S
Müller
Roswitha
R
Pfeilschifter
Josef
J
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats
D016207:Cytokines; D005938:Glucocorticoids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D000242:Cyclic AMP; D020782:Matrix Metalloproteinases