APPROACHES FOR EFFICIENT INHABITION OF INFLAMMATORY GENES BY SMALL DOSES OF CORTICOSTEROIDS

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Glucocorticoids are one of the strongest anti-inflammatory drugs. Long-term use of relatively large doses of glucocorticoids is restricted because of various kinds of adverse effects. This investigation was aimed to develop the way how smaller doses of glucocorticoids efficiently exert strong anti-inflammatory effects. Glucocortiocids clearly inhibited TNF-α-induced IL-6 gene promoter activity in cultured bovine aortic endothelial cells (BAECs), whereas they failed to TNF-α-induced VCAM-1 gene promoter activity in BAECs. However, when glucocorticoid receptor (GR) expression vector was introduced into these cells, glucocorticoids could significantly inhibit TNF-α-induced VCAM-1 gene promoter activity. Interestingly, lower concentrations of glucocorticoids were efficient for the inhibition in high GR expressed cells, compared with low GR expressed cells. These results suggest a potential for strong anti-inflammatory effects of low concentrations of glucocorticoids, by increasing GR expression levels in target cells.Activation of PPARα resulted in inhibition of NF-κB binding to specific sequence of the VCAM-1 gene promoter, indicating the inhibitory effect of PPARα on VCAM-1 gene transcription through inhibition of NF-κB activity. MCC-555,an agonist for PPAR three subtypes, was found to inhibit VCAM-1 expression in vascular endothelial cells and monocytes adhesion to these cells. The PPARδ specific agonist GW501516 could also inhibited VCAM-1 expression, while the PPARγ specific agonist pioglitazone did not. Thus, PPARα and δ, but not γ, have the potential to inhibit the VCAM-1 expression in vascular endothelial cells.Activation of PPARα was also found to increase eNOS protein and its mRNA levels in vascular endothelial cells. PPARα activation failed to increase eNOS gene promoter activity, while it stabilized eNOS mRNA. This observation is interesting for understanding the nuclear receptors-mediated stabilization of mRNA.