Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cyclooxygenase-1 genes in human embryo lung fibroblasts.
In a recent communication, we demonstrated that prostaglandin E2 (PGE2) lowers basal while it ablates interleukin-1beta((IL-1beta) and transforming growth factor-beta (TGFbeta) upregulated lysyl oxidase (LO) mRNA levels. Correspondingly, PGE2 increases cyclooxygenase-1 (COX1) mRNA in diploid, human embryo lung fibroblasts (IMR90) [Roy et al., 19961. We now report that these actions by PGE2 are routed through cAMP via the PGE2, EP2 receptor. Among the PGE2 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 PGE1, an EP2/EP4 agonist, emulates the action of PGE2. In a similar manner to PGE2, 11-deoxy PGE1 decreases basal and TGF-beta induced type I collagen alpha1 (COL) mRNA, basal and IL-1beta 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 PGE2 or 11-deoxy PGE1. It suppresses both basal and TGF-beta induced COL mRNA levels. Both PGE2 and 11-deoxy PGE1 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, PGE2 has little effect on COL mRNA level, whereas forskolin increases it. Furthermore, forskolin increases cAMP level in Rat-1 cells, whereas PGE2 does not. Overall, these results illustrate that much of the PGE2 action on the expression of COL, LO, and COX1 genes is mediated through the EP2 receptor and a subsequent increase in intracellular cAMP.
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
J
J
Choung
L
L
Taylor
K
K
Thomas
X
X
Zhou
H
H
Kagan
X
X
Yang
P
P
Polgar
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D051545:Cyclooxygenase 1; D015232:Dinoprostone / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D007527:Isoenzymes; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016212:Transforming Growth Factor beta; D005576:Colforsin; D003094:Collagen; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D008249:Protein-Lysine 6-Oxidase; D000527:Alprostadil; D015232:Dinoprostone; C034008:11-deoxyprostaglandin E1