PGE2 amplifies the effects of IL-1beta on vascular smooth muscle cell de-differentiation: a consequence of the versatility of PGE2 receptors 3 due to the emerging expression of adenylyl cyclase 8.
Transition of vascular smooth muscle cells from a contractile/quiescent to a secretory/proliferative phenotype is one of the critical steps in atherosclerosis and is instigated by pro-inflammatory cytokines released from macrophages that have infiltrated into the vascular wall. In most inflammatory diseases, cell activation induced by these compounds leads to a massive production of type E2 prostaglandin (PGE2) which often takes over and even potentiates the pro-inflammatory cytokine-related effects. To evaluate PGE2 incidence on atheroma plaque development, we investigated whether and how this compound could enhance the dedifferentiation of smooth muscle cells initially induced by interleukin-1beta (IL-1beta). To address this issue, we took advantage of vascular smooth muscle cells in primary culture and tracked two markers: PLA2 secretion and alpha-actin filament disorganization. In such a context, we found that PGE2 synergizes with IL-1beta to further enhance the phenotype transition of smooth muscle cells, through cAMP-protein kinase A. As indicated by pharmacological studies, the full PGE2-dependent potentiation of IL-1beta induced PLA2 secretion is associated with a change of regulation exerted by the subtypes 3 G(i)-coupled PGE2 receptors toward adenylyl cyclase(s) activated by the subtype 4 G(s)-linked PGE2 receptor. Whereas on contractile cells, stimulated subtypes 3 inhibit type 4-dependent PLA2 secretion, this negative regulation is switched to positive on IL-1beta-treated cells. Using real time PCR, pharmacological tools and small interfering RNA (siRNA), we demonstrated that the different integration of PGE2 signals depends on the upregulation of calcium/calmodulin stimulable adenylyl cyclase 8.
Clément
Nathalie
N
UMR 7079 CNRS, Université Pierre et Marie Curie (UPMC-Paris 6), Paris, France.
Glorian
Martine
M
Raymondjean
Michel
M
Andréani
Marise
M
Limon
Isabelle
I
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism; D054467:Phospholipases A2; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000145:classification / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D007375:Interleukin-1; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D000242:Cyclic AMP; D010741:Phospholipases A; D054467:Phospholipases A2; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D015232:Dinoprostone