Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen α1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts
✍ Scribed by J. Choung; L. Taylor; K. Thomas; X. Zhou; H. Kagan; X. Yang; P. Polgar
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 178 KB
- Volume
- 71
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
In a recent communication, we demonstrated that prostaglandin E 2 (PGE 2 ) lowers basal while it ablates interleukin-1( (IL-1) and transforming growth factor- (TGF) upregulated lysyl oxidase (LO) mRNA levels. Correspondingly, PGE 2 increases cyclooxygenase-1 (COX1) mRNA in diploid, human embryo lung fibroblasts (IMR90) [Roy et al., 1996]. We now report that these actions by PGE 2 are routed through cAMP via the PGE 2 , EP2 receptor. Among the PGE 2 receptor types, the IMR90 predominantly express the EP2 mRNA. These cells also express EP3 and EP4 mRNA at comparatively low levels. Northern blot analyses show that 11-deoxy PGE 1 , an EP2/EP4 agonist, emulates the action of PGE 2 . In a similar manner to PGE 2 , 11-deoxy PGE 1 decreases basal and TGF- induced type I collagen ␣1 (COL) mRNA, basal and IL-1 induced LO mRNA while it increases COX1 mRNA. Sulprostone, an EP3/EP1 agonist, has no effect on the expression of these three genes. Forskolin, an adenylate cyclase activator, acts in a very similar manner to PGE 2 or 11-deoxy PGE 1 . It suppresses both basal and TGF- induced COL mRNA levels. Both PGE 2 and 11-deoxy PGE 1 increase cAMP to a level comparable with forskolin. The role of the EP2 receptor in controlling collagen production is further underscored in the immortalized Rat-1 fibroblasts, derived from Fischer rat embryos, which do not express detectable EP2 mRNA. In these cells, PGE 2 has little effect on COL mRNA level, whereas forskolin increases it. Furthermore, forskolin increases cAMP level in Rat-1 cells, whereas PGE 2 does not. Overall, these results illustrate that much of the PGE 2 action on the expression of COL, LO, and COX1 genes is mediated through the EP2 receptor and a subsequent increase in intracellular cAMP.