Regulatory role of prostaglandin E2 in induction of cyclo-oxygenase-2 by a thromboxane A2 analogue (U46619) and basic fibroblast growth factor in porcine aortic smooth-muscle cells

Abstract

U46619, a thromboxane A2 analogue, and basic fibroblast growth factor (FGF-2) both induced the expression of the inducible cyclo-oxygenase (Cox)-2 in porcine aortic smooth-muscle cells. This induction was dose-dependent (submaximal at 300 nM for U46619 and 1 ng/ml for FGF-2) and time-dependent, with similar intensity and maximal expression at 2 h. Under these conditions, both inducers stimulated rapid activation of extracellular signal-regulated kinase (ERK2) at 5-10 min, a transient and lower intensity being induced by U46619 whereas that induced by FGF-2 was sustained (>1 h). PD98059, an inhibitor of the ERK pathway, inhibited the expression of Cox-2. In contrast, activation of Jun-N-terminal kinase (JNK1) was sustained with U46619 but poorly induced by FGF-2. Cox-2 expression induced by U46619 or FGF-2 was similarly reduced by prostaglandin (PGE2), forskolin or dibutyryl-cAMP, suggesting a regulatory effect of adenylate cyclase on Cox-2 expression. However, activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited, suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2. The effects of PGE2 and forskolin on Cox-2 and phosphorylation of JNK1 were reversed with the protein kinase A inhibitor H89. In addition, endogenous PGE2 down-regulated the expression of Cox-2 by the two inducers, as stimulation of the cells in the presence of different Cox inhibitors increased the expression of the protein. Overall, these results suggest that exogenous and endogenous PGE2 exert negative inhibitory effects on Cox-2 expression mediated by stimulation of protein kinase A.

Prostaglandin E2 drives cyclooxygenase 2 expression via cyclic AMP response element activation in human pancreatic cancer cells

“…Our results differ from those of researchers who reported that PGE 2 or other cAMP production-elevating agents inhibited COX-2 expression via stimulation of PKA. Karim et al 41 found that PKA inhibited the phosphorylation of c-Jun transcription factor by c-Jun NH2-terminal kinase, which led to inhibition of c-Jun-mediated COX-2 transcription in porcine aortic smooth muscle cells; this effect was reversed by inhibition of the PKA activity. Reddy et al 42 observed that PGE 2 suppressed C/EBPβ-mediated COX-2 transcription by activating PKA in murine mast cells.…”

Modulation of Cell-Substrate Adhesion by Arachidonic Acid: Lipoxygenase Regulates Cell Spreading and ERK1/2-inducible Cyclooxygenase Regulates Cell Migration in NIH-3T3 Fibroblasts

“…It is reasonable to propose that COX-2 expression is induced during cell adhesion because ERK1/2 is activated during adhesion, and induction of COX-2 expression by growth-factor mitogens is mediated by ERK1/2 (Miyamoto et al, 1996;Cybulsky and McTavish, 1997;Hwang et al, 1997;Karim et al, 1997;Langholz et al, 1997;Bourdoulous et al, 1998;Miller et al, 1998;Sheng et al, 1998;Adderley and Fitzgerald, 1999). Our measurements indicate that COX-2 protein appeared in control cells at ϳ45-60 min postplating, after spreading was essen-tially complete, whereas blockade of ERK1/2 prevented induction and synthesis of COX-2 ( Figure 10B).…”

Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice

“…23 Real-time polymerase chain reaction (PCR) analysis of lesions from SU5402 and vehicle-treated mice (supplemental Figure IV) indicated large reductions in the expression of mRNAs encoding HAS-1 (Ϸ68%) and HAS-2 (Ϸ85%) after inhibition of FGFR signaling. Similarly, the level of the oxLDL receptor CD36 mRNA, the expression of which is known to increase when monocytes interact with SMCs, 24 was reduced by Ϸ90%. Strikingly, cyclooxygenase-2 (COX-2), the expression of which also enhances SMCmonocyte interactions 20 and which can be induced by FGF-2 in SMCs, 24 was almost completely abolished by treatment with SU5402.…”

“…Similarly, the level of the oxLDL receptor CD36 mRNA, the expression of which is known to increase when monocytes interact with SMCs, 24 was reduced by Ϸ90%. Strikingly, cyclooxygenase-2 (COX-2), the expression of which also enhances SMCmonocyte interactions 20 and which can be induced by FGF-2 in SMCs, 24 was almost completely abolished by treatment with SU5402. Finally, endothelial monocyte-activating polypeptide-II (EMAP-II), which can also promote binding of monocytes to SMCs, 25 was also reduced in expression after inhibition of FGFR signaling, although to a lesser extent (Ϸ45%) than the other retention factors.…”