Role of prostaglandin E(2) EP receptors and cAMP in the expression of connective tissue growth factor.
Wild-type (WT) Rat-1 fibroblasts express undetectable quantities of the prostaglandin E(2) (PGE(2)) EP1, EP2, and EP3 receptor types and detectable amounts of the EP4 receptor. In the WT Rat-1, PGE(2) enhances connective tissue growth factor (CTGF) mRNA. PGE(2) does not stimulate cAMP production in these cells. However, forskolin induces cAMP production and ablates TGF beta-stimulated increases in CTGF mRNA. A similar pattern of CTGF expression in response to PGE(2) and forskolin is observed in neonatal rat primary smooth muscle cell cultures. When WT Rat-1 cells are stably transfected with the EP2 receptor, PGE(2) causes a sizable elevation in intracellular cAMP and ablates the TGF beta-stimulated increase in CTGF mRNA. PGE(2) does not have this effect on cells expressing the EP1, EP3, or EP4 receptor subtypes. These results demonstrate the importance of the EP2 receptor and cAMP in the inhibition of TGF beta-stimulated CTGF production and suggest a role for PGE(2) in increasing CTGF mRNA levels in the absence of the EP2 receptor. Involvement of inositol phosphate in this upregulation of CTGF expression by PGE(2) is doubtful. None of the cell lines containing the four EP transfectants nor the WT Rat-1 cells responded to PGE(2) with inositol phosphate production.
Yu
Jun
J
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Prado
Gregory N
GN
Schreiber
Barbara
B
Polgar
Paul
P
Polgar
Peter
P
Taylor
Linda
L
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D010716:Phosphatidylinositols / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526316:CCN2 protein, rat; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010716:Phosphatidylinositols; C545637:Ptger1 protein, rat; C545646:Ptger2 protein, rat; C545649:Ptger3 protein, rat; C545652:Ptger4 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP; D015232:Dinoprostone