TETRANACTIN INHIBITS INTERLEUKIN-1-BETA AND CAMP INDUCTION OF GROUP-II PHOSPHOLIPASE A(2) IN RAT RENAL MESANGIAL CELLS

Renal mesangial cells express secretory phospholipase A(2) in response to two principal classes of activating signals that may interact in a synergistic fashion. These two groups of activators comprise inflamma tory cytokines, such as interleukin 1 beta, and agents that elevate ce llular levels of cAMP. Treatment of mesangial cells with tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular s tructure similar to cyclosporin A inhibits interleukin 1 beta- and cAM P-dependent group II phospholipase A(2) secretion in a dose-dependent manner with IC50 values of 43 and 33 nM, respectively. However, tetran actin does not directly inhibit group II phospholipase A(2) activity. Western blot analyses of mesangial cell supernatants reveal that the i nhibition of phospholipasl A(2) activity is due to suppression of phos pholipase A(2) protein synthesis. This effect is preceded by the reduc tion of phospholipase A(2) mRNA steady-state levels as shown by Northe rn blot analyses of total cellular RNA isolated from stimulated mesang ial cells. Thus, tetranactin is a potent inhibitor of group II phospho lipase A(2) expression in cytokine- and cAMP-stimulated mesangial cell s and represents a new class of group II phospholipase A(2) inhibitors with IC50 values in the low nanomolar range. This compound may be use ful in the therapy of diseases associated with increased group II phos pholipase A(2) secretion.