Tetranactin inhibits interleukin 1β and cAMP induction of group II phospholipase A2 in rat renal mesangial cells

Abstract 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 inflammatory cytokines, such as interleukin 1β, and agents that elevate cellular levels of cAMP. Treatment of mesangial cells with tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure similar to cyclosporin A inhibits interleukin 1β- and cAMP-dependent group II phospholipase A 2 secretion in a dose-dependent manner with IC 50 values of 43 and 33 nM, respectively. However, tetranactin does not directly inhibit group II phospholipase A 2 activity. Western blot analyses of mesangial cell supernatants reveal that the inhibition of phospholipase A 2 activity is due to suppression of phospholipase A 2 protein synthesis. This effect is preceded by the reduction of phospholipase A 2 mRNA steady-state levels as shown by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. Thus, tetranactin is a potent inhibitor of group II phospholipase A 2 expression in cytokine- and cAMP-stimulated mesangial cells and represents a new class of group II phospholipase A 2 inhibitors with IC 50 values in the low nanomolar range. This compound may be useful in the therapy of diseases associated with increased group II phospholipase A 2 secretion.