TY - JOUR
T1 - CD73-dependent adenosine dampens interleukin-1β–induced CXCL8 production in gingival fibroblasts
T2 - Association with heme oxygenase-1 and adenosine monophosphate–activated protein kinase
AU - Ramos-Junior, Erivan Schnaider
AU - Pedram, Michael
AU - Lee, Renee E.
AU - Exstrom, Drake
AU - Yilmaz, Özlem
AU - Coutinho-Silva, Robson
AU - Ojcius, David M.
AU - Morandini, Ana Carolina
N1 - Funding Information:
This study was supported by Start-Up Funds and Research Enhancement Award (DRES 03-Activity 117, 2017 to ACM) from the University of the Pacific, Arthur A. Dugoni School of Dentistry, and funding from the NIDCR grant R01DE016593. The results of this study were presented as a poster at the American Association of Immunologists Meeting in San Diego, California, in May 2019. The authors report no conflicts of interest related to this study.
Publisher Copyright:
© John Wiley and Sons Inc. All rights reserved.
PY - 2020
Y1 - 2020
N2 - Background: During inflammation, stressed or infected cells can release adenosine triphosphate (ATP) to the extracellular medium, which can be hydrolyzed to adenosine by ectonucleotidases such as ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5′-nucleotidase (CD73). The role of CD73 in the modulation of cytokine release by human gingival fibroblasts (HGFs) remains underexplored. Here, we investigated whether CD73-mediated hydrolysis of extracellular ATP (eATP) could affect interleukin (IL)-1B-induced CXCL8 secretion. Methods: The levels of mRNA expression of adenosine receptors, CD39 and CD73 of periodontitis samples were retrieved from a public database. Moreover, HGF mRNA levels were measured by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) after 3, 6, or 24 hours of IL-1B stimulation. IL-1B-induced CXCL8 protein levels were measured after pretreatment with 100-µM eATP in the presence or absence of CD73 inhibitor. The effect of eATP degradation to adenosine on CXCL8 levels was investigated using agonist and antagonist of adenosine receptors. Results: Levels of CD39, CD73, and adenosine receptor mRNA were differentially modulated by IL-1B. ATP pretreatment impaired IL-1B-induced CXCL8 secretion and required activation of heme oxygenase-1 (HO-1) and phosphorylated adenosine monophosphate–activated protein kinase (pAMPK). The inhibition of CD73 or the inhibition of adenosine receptors abrogated the ATP effect on CXCL8 secretion. Conclusions: CD73-generated adenosine dampens IL-1B-induced CXCL8 in HGFs and involves HO-1 and pAMPK signaling. These results imply that CD73 is a negative regulator of the inflammatory microenvironment, suggesting that this ectoenzyme could be involved in the generation of deficient CXCL8 gradient in chronic inflammation.
AB - Background: During inflammation, stressed or infected cells can release adenosine triphosphate (ATP) to the extracellular medium, which can be hydrolyzed to adenosine by ectonucleotidases such as ectonucleoside triphosphate diphosphohydrolase 1 (CD39) and 5′-nucleotidase (CD73). The role of CD73 in the modulation of cytokine release by human gingival fibroblasts (HGFs) remains underexplored. Here, we investigated whether CD73-mediated hydrolysis of extracellular ATP (eATP) could affect interleukin (IL)-1B-induced CXCL8 secretion. Methods: The levels of mRNA expression of adenosine receptors, CD39 and CD73 of periodontitis samples were retrieved from a public database. Moreover, HGF mRNA levels were measured by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) after 3, 6, or 24 hours of IL-1B stimulation. IL-1B-induced CXCL8 protein levels were measured after pretreatment with 100-µM eATP in the presence or absence of CD73 inhibitor. The effect of eATP degradation to adenosine on CXCL8 levels was investigated using agonist and antagonist of adenosine receptors. Results: Levels of CD39, CD73, and adenosine receptor mRNA were differentially modulated by IL-1B. ATP pretreatment impaired IL-1B-induced CXCL8 secretion and required activation of heme oxygenase-1 (HO-1) and phosphorylated adenosine monophosphate–activated protein kinase (pAMPK). The inhibition of CD73 or the inhibition of adenosine receptors abrogated the ATP effect on CXCL8 secretion. Conclusions: CD73-generated adenosine dampens IL-1B-induced CXCL8 in HGFs and involves HO-1 and pAMPK signaling. These results imply that CD73 is a negative regulator of the inflammatory microenvironment, suggesting that this ectoenzyme could be involved in the generation of deficient CXCL8 gradient in chronic inflammation.
KW - 5-nucleotidase
KW - adenosine
KW - adenosine triphosphate
KW - fibroblasts
KW - gingiva
KW - interleukin-1 beta
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U2 - 10.1002/JPER.19-0137
DO - 10.1002/JPER.19-0137
M3 - Article
C2 - 31347162
AN - SCOPUS:85079563972
SN - 0022-3492
VL - 91
SP - 253
EP - 262
JO - Journal of Periodontology
JF - Journal of Periodontology
IS - 2
ER -