EFFECT OF OKADAIC ACID ON ELASTIN GENE-EXPRESSION IN INTERSTITIAL LUNG FIBROBLASTS

Okadaic acid (OA), a specific serine/threonine protein phosphatase inh ibitor, downregulated tropoelastin formation and elastin mRNA levels i n a dose-related and cycloheximide-sensitive fashion in cultured lung fibroblasts. Treatment with a tyrosine phosphatase inhibitor at high c oncentrations did not alter elastin mRNA levels, however. Nuclear run- on analysis indicated that OA primarily suppressed elastin gene expres sion through a transcriptional mechanism. In contrast to its effects o n elastin expression, OA downregulated alpha(1)(I) mRNA to significant ly lesser degrees. The mechanism by which OA decreased elastin mRNA le vels did not appear to involve protein kinase C or share the signaling pathway of IL-1 beta. Prolonged treatment with phorbol ester promoted the inhibitory effects of OA on elastin, as did shorter treatment wit h IL-1 beta. Moreover, transient transfection studies indicated that O A and IL-1 beta do not act through the same cis-acting element in the elastin promoter. Finally, unlike the transient effects of IL-1 beta, OA induced persistent inhibition of elastin expression by a transcript ional mechanism. Taken together, these data indicate that serine/threo nine protein phosphorylation can regulate the amount and composition o f extracellular matrix secreted by fibroblasts into the interstitium o f the lung.