Cyclooxygenase-2-derived prostaglandin E2 is involved in vascular endothelial growth factor production in interleukin-1alpha-stimulated human periodontal ligament cells.
OBJECTIVE
Prostaglandin E(2), which exerts its actions via EP receptors (EP1, EP2, EP3 and EP4), is a bioactive metabolite of arachidonic acid produced by cyclooxygenase-1 and/or cyclooxygenase-2. Interleukin-1alpha induces prostaglandin E(2) production via cyclooxygenase-2 in human periodontal ligament cells. Vascular endothelial growth factor is a key regulator of physiologic as well as pathologic angiogenesis and has been indicated to be involved in the pathology of periodontal diseases. In the present study, we investigated whether interleukin-1alpha induced vascular endothelial growth factor production in human periodontal ligament cells and whether cyclooxygenase-2-derived prostaglandin E(2) regulated interleukin-1alpha-induced vascular endothelial growth factor production.


METHODS
Human periodontal ligament cells were obtained from extracted teeth of periodontally healthy subjects. After pre-incubation with a nonselective cyclooxygenase-1/2 inhibitor, indomethacin or a selective cyclooxygenase-2 inhibitor (NS-398), periodontal ligament cells were treated with or without interleukin-1alpha, prostaglandin E(2), various EP receptor agonists and dibutyryl cAMP (a cAMP analogue). The levels of vascular endothelial growth factor and prostaglandin E(2) in the culture supernatant were measured by enzyme-linked immunosorbent assay. The vascular endothelial growth factor mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction.


RESULTS
Interleukin-1alpha induced vascular endothelial growth factor production in a dose-dependent and time-dependent manner. The interleukin-1alpha-induced vascular endothelial growth factor mRNA and protein expression was inhibited to the same extent by indomethacin and NS-398. Indomethacin and NS-398 completely inhibited interleukin-1alpha-induced prostaglandin E(2) production. Exogenous prostaglandin E(2), butaprost (an EP2 receptor agonist) and dibutyryl cAMP abolished the inhibitory effect of indomethacin on interleukin-1alpha-induced vascular endothelial growth factor production.


CONCLUSIONS
We suggest that interleukin-1alpha induced vascular endothelial growth factor production via cyclooxygenase-2-derived prostaglandin E(2) in human periodontal ligament cells. The interleukin-1alpha/prostaglandin E(2) pathway might regulate vascular endothelial growth factor production in periodontal lesions.
Bando
Y
Y
Periodontology, Department of Hard Tissue Engineering, Tokyo Medical and Dental University, Tokyo, Japan. u-bando.peri@tmd.ac.jp
Noguchi
K
K
Kobayashi
H
H
Yoshida
N
N
Ishikawa
I
I
Izumi
Y
Y
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000494:pharmacology / Q000502:physiology*; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D052246:Cyclooxygenase 2 Inhibitors; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007213:Indomethacin