Regulation of lysyl oxidase and cyclooxygenase expression in human lung fibroblasts: interactions among TGF-beta, IL-1 beta, and prostaglandin E.

Prostaglandin E2, transforming growth factor-beta, and interleukin-1 beta variably regulate the expression of cyclooxygenase 1, cyclooxygenase 2, and lysyl oxidase in IMR90, human embryo lung fibroblasts. Prostaglandin E2 at 100 nM upregulates cyclooxygenase 1 mRNA by approximately three-fold while it downregulates lysyl oxidase mRNA levels. Notably, prostaglandin E2 suppresses the enhancing effect of TGF-beta on basal levels of lysyl oxidase mRNA. These changes in steady state mRNA levels reflect transcriptional level control, at least in part. Corresponding changes are seen in the protein levels of lysyl oxidase, cyclooxygenase 1 and cyclooxygenase 2 and catalytic activities of these enzymes, including net prostaglandin E2 synthesis. Cyclooxygenase 2 mRNA(t1/2, 30 min) is considerably less stable than that of cyclooxygenase 1 (t1/2, 4 h) while lysyl oxidase mRNA is unusually stable (t1/2 > 14 h). Taken together with the differing kinetics with which these genes respond to perturbation by these cytokines, the present results suggest a coordinated, autocrine-like mechanism of regulation of cyclooxygenase 1 and cyclooxygenase 2 and further point to the potential of their metabolic product, prostaglandin E2, to suppress the expression of lysyl oxidase in the inflammatory response to injury.