Inhibitors of protein and RNA synthesis cause a rapid block in prostaglandin production at the prostaglandin synthase step

Abstract

Inhibitors of protein or RNA synthesis prevented prostaglandin (PG) production in isolated skeletal muscles, brain, and spleen. Incubation of rat muscles with cycloheximide prevented the stimulation of PGE2 production induced in vitro by the Ca2+ ionophore A23187 and in vivo by injection of endotoxin. Cycloheximide also inhibited the stimulation by arachidonic acid of PGE2, PGF2 alpha, and prostacyclin. These observations suggest that the block in prostanoid production results from a loss of PG synthase activity (EC 1.14.99.1). These effects were detectable within 10 min after exposure of the muscle to cycloheximide. The degree of inhibition of PG production correlated with the degree of inhibition of protein synthesis. Other inhibitors of protein synthesis, puromycin and emetine, also prevented conversion of arachidonate into PGE2 in these tissues, but they did not inhibit purified PG synthase. Exposure of muscles to actinomycin D for 20 min also reduced PGE2 production from arachidonate by 90%. Thus, both the PG synthase and its mRNA appear to be inactivated rapidly (t1/2 less than 10 min) in muscle and other mammalian tissues. The block in PG production induced by inhibitors of protein and RNA synthesis may account for their antipyrogenic actions and certain of their other physiological effects.