Extracellular ATP inhibits IL-1-induced MMP-1 expression through the action of CD39/nucleotidase triphosphate dephosphorylase-1 on human gingival fibroblasts.
Extracellular adenosine triphosphate (ATP) is sequentially dephosphorylated by two ectoenzymes: CD39/nucleotidase triphosphate dephosphorylase (ENTPD) and CD73/5'-ectonucleotidase (5'-NT). Adenosine, its notable metabolite, may elicit potent anti-inflammatory responses. We examined whether the CD39-adenosinergic axis may exist in gingival fibroblasts and have an effect on the expression of matrix metalloproteinase (MMP)-1, the excess production of which leads to pathological matrix degradation. We showed that transcripts of CD39, CD73, and adenosine receptors A1, A2a, and A2b, but not A3, were expressed by human gingival fibroblasts by RT-PCR. We also identified the expression of CD39 in fibroblastic cells in rat gingiva by immunohistochemistry. ATP inhibited the expression of MMP-1 triggered by interleukin-1 at gene and protein levels. However, ATP-γS, a stable ATP analog, did not. The ATP-mediated MMP-1 inhibition was restored in the presence of POM-1, a specific ENTPD inhibitor, suggesting that CD39/ENTPD was involved in the MMP-1 inhibition. ATP metabolites including adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), and adenosine inhibited MMP-1 expression, but ADP-βS, a stable ADP, did not, suggesting that adenosine converted from ATP by the action of CD39/ENTPD and CD73/5'-NT may contribute to MMP-1 inhibition. Adenosine-mediated MMP-1 inhibition was restored in the presence of H89, a protein kinase A (PKA) inhibitor. Conversely, forskolin, an enhancer of intracellular cAMP, mimicked the effect of adenosine, suggesting that the cAMP/PKA signaling pathway is involved in adenosine-mediated MMP-1 inhibition. The present findings suggest the existence of an endogenous anti-tissue destructive mechanism in gingival tissue via the CD39-adenosinergic axis.
Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi Aoba, Sendai 980-8575, Japan. Electronic address: e-nemoto@dent.tohoku.ac.jp.
Eiji
E
Nemoto
Kazuhiro
K
Gotoh
Masahiro
M
Tsuchiya
Yukihiko
Y
Sakisaka
Hidetoshi
H
Shimauchi
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D017973:Tungsten Compounds / Q000494:pharmacology; D055815:Young Adult
D015703:Antigens, CD; D007375:Interleukin-1; D017973:Tungsten Compounds; C040585:sodium metatungstate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D001081:Apyrase; C067869:CD39 antigen
ATP; CD39; Ectoenzyme; Gingival fibroblast; Inflammation; Matrix metalloproteinase