Effect of okadaic acid on elastin gene expression in interstitial lung fibroblasts
Berk, J.L.; Massoomi, N.; Krupsky, M.; Goldstein, R.H.
American Journal of Physiology 271(6 Pt 1): L939-L948
1996
ISSN/ISBN: 0002-9513 PMID: 8997264 Document Number: 467352
Okadaic acid (OA), a specific serine/threonine protein phosphatase inhibitor, downregulated tropoelastin formation and elastin mRNA levels in a dose-related and cycloheximide-sensitive fashion in cultured lung fibroblasts. Treatment with a tyrosine phosphatase inhibitor at high concentrations did not alter elastin mRNA levels, however. Nuclear run-on analysis indicated that OA primarily suppressed elastin gene expression through a transcriptional mechanism. In contrast to its effects on elastin expression, OA downregulated alpha-1(I) mRNA to significantly lesser degrees. The mechanism by which OA decreased elastin mRNA levels 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 with IL-1-beta. Moreover, transient transfection studies indicated that OA 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 transcriptional mechanism. Taken together, these data indicate that serine/threonine protein phosphorylation can regulate the amount and composition of extracellular matrix secreted by fibroblasts into the interstitium of the lung.