PROBUCOL INHIBITS INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION ON CULTURED RAT MESANGIAL CELLS

Interleukin-1 (IL-1) has been reported to participate in the progressi on of glomerulonephritis by, in part, up-regulating intercellular adhe sion molecule-1 (ICAM-1) expression in experimental glomerulonephritis . In the present study, we examined whether probucol, an antihyperlipi demic agent, inhibited IL-1-induced inflammatory processes in mesangia l cells in culture. Northern blot analysis demonstrated that 200 U/mL IL-1 up-regulated ICAM-1 messenger RNA (mRNA) expression with its peak at 4-6 h after stimulation. Ten mu g/mL lipopolysaccharide (LPS), a s timulant to release IL-1 from mesangial cells, induced ICAM-1 mRNA exp ression by five-fold within 6 h and 10 mu g/mL probucol notably reduce d this induction. Immunoblotting also confirmed that LPS increased ICA M-1 protein by two-fold within 24 h and probucol inhibited this increa se. IL-1 receptor antagonist (IL-1ra; 1-100 ng/mL) suppressed LPS-indu ced ICAM-1 mRNA expression in a dose-dependent manner and 100 ng/mL IL -1ra completely inhibited ICAM-1 induction, indicating that LPS increa sed ICAM-1 expression through the action of secreted IL-1. Interleukin -1 activity in culture media, measured by thymocyte proliferation assa y, was significantly enhanced by LPS and inhibited by probucol. Howeve r, neither LPS nor probucol substantially affected IL-1 mRNA expressio n, suggesting that the IL-1 activity might be regulated at post-transl ational level. These results suggest that probucol may act as an anti- inflammatory drug by suppressing IL-1 activity from mesangial cells in the progression of glomerulonephritis.