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AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells

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Abstract

Objectives

To determine the role of angiogenic factor with G-patch and FHA domain 1 (AGGF1) in inflammatory response of human dental pulp cells (DPCs) and the underneath mechanism and to explore its role in angiogenesis.

Materials and methods

The expression of AGGF-1 in human healthy and inflammatory pulp tissues was detected by immunohistochemistry. RT-qPCR and Western blot were used to evaluate the expression of AGGF1 in DPCs stimulated by lipopolysaccharide (LPS). After AGGF1 was knocked down, the expression of LPS-induced inflammatory cytokines in DPCs was quantified by RT-qPCR and ELISA. Immunofluorescence and Western blot were used to assess the activation of NF-κB signaling. Inflammatory cytokines were detected by RT-qPCR and ELISA in DPCs pretreated with NF-κB pathway inhibitors before LPS stimulation, and then the effect of AGGF1 on angiogenesis was also evaluated.

Results

AGGF1 expression increased in inflammatory dental pulp tissues. In DPCs stimulated by LPS, AGGF1 was upregulated in a dose-dependent manner (P < 0.05). In AGGF1 knockdown cells, the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1/CCL-2) increased by LPS stimulation (P < 0.001). Nuclear translocation of p65 was promoted, and the addition of NF-κB inhibitors inhibited the expression of inflammatory factors. Meanwhile, knockdown of AGGF1 inhibited vascularization.

Conclusions

AGGF1 inhibited the synthesis of inflammatory cytokines through NF-κB signaling pathway and promoted the angiogenesis of DPCs.

Clinical relevance

This study might shed light in the treatment of pulpitis and regeneration of dental pulp tissues; however, more clinical trials are required to validate these findings.

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References

  1. Caplan DJ, Cai J, Yin G, White BA (2005) Root canal filled versus non-root canal filled teeth: a retrospective comparison of survival times. J Public Health Dent 65:90–96

    Article  PubMed  Google Scholar 

  2. Bergenholtz G (1981) Inflammatory response of the dental pulp to bacterial irritation. J Endod 7:100–104

    Article  PubMed  Google Scholar 

  3. Keller JF, Carrouel F, Staquet MJ, Kufer TA, Baudouin C, Msika P, Bleicher F, Farges JC (2011) Expression of NOD2 is increased in inflamed human dental pulps and lipoteichoic acid-stimulated odontoblast-like cells. Innate Immun 17:29–34

    Article  PubMed  Google Scholar 

  4. Staquet MJ, Carrouel F, Keller JF, Baudouin C, Msika P, Bleicher F, Kufer TA, Farges JC (2011) Pattern-recognition receptors in pulp defense. Adv Dent Res 23:296–301

    Article  PubMed  Google Scholar 

  5. Tecles O, Laurent P, Zygouritsas S, Burger AS, Camps J, Dejou J, About I (2005) Activation of human dental pulp progenitor/stem cells in response to odontoblast injury. Arch Oral Biol 50:103–108

    Article  PubMed  Google Scholar 

  6. Stashenko P (1990) Role of immune cytokines in the pathogenesis of periapical lesions. Endod Dent Traumatol 6:89–96

    Article  PubMed  Google Scholar 

  7. Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683

    Article  PubMed  Google Scholar 

  8. Hu FY, Wu C, Li Y, Xu K, Wang WJ, Cao H, Tian XL (2013) AGGF1 is a novel anti-inflammatory factor associated with TNF-alpha-induced endothelial activation. Cell Signal 25:1645–1653

    Article  PubMed  Google Scholar 

  9. Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q (2004) Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature 427:640–645

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen D, Li L, Tu X, Yin Z, Wang Q (2013) Functional characterization of Klippel-Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis. Hum Mol Genet 22:963–976

    Article  PubMed  Google Scholar 

  11. Zhou B, Zeng S, Li L, Fan Z, Tian W, Li M, Xu H, Wu X, Fang M, Xu Y (2016) Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-beta signaling. Biochim Biophys Acta 1862:1203–1213

    Article  PubMed  Google Scholar 

  12. Fan C, Ouyang P, Timur AA, He P, You SA, Hu Y, Ke T, Driscoll DJ, Chen Q, Wang QK (2009) Novel roles of GATA1 in regulation of angiogenic factor AGGF1 and endothelial cell function. J Biol Chem 284:23331–23343

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xu W, Zeng S, Li M, Fan Z, Zhou B (2017) Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription. J Biomed Res 31:428–436

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lu Q, Yao Y, Hu Z, Hu C, Song Q, Ye J, Xu C, Wang AZ, Chen Q, Wang QK (2016) Angiogenic factor AGGF1 activates autophagy with an essential role in therapeutic angiogenesis for heart disease. PLoS Biol 14:e1002529

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kim JY, Xin X, Moioli EK, Chung J, Lee CH, Chen M, Fu SY, Koch PD, Mao JJ (2010) Regeneration of dental-pulp-like tissue by chemotaxis-induced cell homing. Tissue Eng Part A 16:3023–3031

    Article  PubMed  PubMed Central  Google Scholar 

  16. Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, DenBesten P, Robey PG, Shi S (2002) Stem cell properties of human dental pulp stem cells. J Dent Res 81:531–535

    Article  PubMed  Google Scholar 

  17. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 97:13625–13630

    Article  PubMed  PubMed Central  Google Scholar 

  18. Huang GT, Gronthos S, Shi S (2009) Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res 88:792–806

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tran-Hung L, Laurent P, Camps J, About I (2008) Quantification of angiogenic growth factors released by human dental cells after injury. Arch Oral Biol 53:9–13

    Article  PubMed  Google Scholar 

  20. Wang W, Li GY, Zhu JY, Huang DB, Zhou HC, Zhong W, Ji CS (2015) Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma. Med Oncol 32:131

    Article  PubMed  Google Scholar 

  21. Doyon GE, Dumsha T, von Fraunhofer JA (2005) Fracture resistance of human root dentin exposed to intracanal calcium hydroxide. J Endod 31:895–897

    Article  PubMed  Google Scholar 

  22. Murray PE, Garcia-Godoy F, Hargreaves KM (2007) Regenerative endodontics: a review of current status and a call for action. J Endod 33:377–390

    Article  PubMed  Google Scholar 

  23. Fouad AF (2011) The microbial challenge to pulp regeneration. Adv Dent Res 23:285–289

    Article  PubMed  PubMed Central  Google Scholar 

  24. Goldberg M, Schmalz G (2011) Toward a strategic plan for pulp healing: from repair to regeneration. Clin Oral Investig 15:1–2

    Article  PubMed  Google Scholar 

  25. Love RM, Jenkinson HF (2002) Invasion of dentinal tubules by oral bacteria. Crit Rev Oral Biol Med 13:171–183

    Article  PubMed  Google Scholar 

  26. Hosoya S, Matsushima K (1997) Stimulation of interleukin-1 beta production of human dental pulp cells by Porphyromonas endodontalis lipopolysaccharide. J Endod 23:39–42

    Article  PubMed  Google Scholar 

  27. Graves DT, Oates T, Garlet GP (2011) Review of osteoimmunology and the host response in endodontic and periodontal lesions. J Oral Microbiol 3

  28. Levin LG, Law AS, Holland GR, Abbott PV, Roda RS (2009) Identify and define all diagnostic terms for pulpal health and disease states. J Endod 35:1645–1657

    Article  PubMed  Google Scholar 

  29. Wu H, He M, Yang R, Zuo Y, Bian Z (2018) Astrocyte elevated gene-1 participates in the production of pro-inflammatory cytokines in dental pulp cells via NF-κB signalling pathway. Int Endod J 51:1130–1138

    Article  PubMed  Google Scholar 

  30. Qiao W, Huang Y, Bian Z, Sun X, Wang X, Gao Q, Peng Y, Meng L (2019) Lipopolysaccharide-induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells. Int Endod J 52:1704–1715

    Article  PubMed  Google Scholar 

  31. Bucklin SE, Morrison DC (1995) Differences in therapeutic efficacy among cell wall-active antibiotics in a mouse model of gram-negative sepsis. J Infect Dis 172:1519–1527

    Article  PubMed  Google Scholar 

  32. Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819

    Article  PubMed  Google Scholar 

  33. Remick DG (2005) Interleukin-8. Crit Care Med 33:S466–S467

    Article  PubMed  Google Scholar 

  34. Zehnder M, Delaleu N, Du Y, Bickel M (2003) Cytokine gene expression—part of host defence in pulpitis. Cytokine 22:84–88

    Article  PubMed  Google Scholar 

  35. Long XH, Zhao ZQ, He XP, Wang HP, Xu QZ, An J, Bai B, Sui JL, Zhou PK (2007) Dose-dependent expression changes of early response genes to ionizing radiation in human lymphoblastoid cells. Int J Mol Med 19:607–615

    PubMed  Google Scholar 

  36. Hu Y, Li L, Seidelmann SB, Timur AA, Shen PH, Driscoll DJ, Wang QK (2008) Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program. Ann Hum Genet 72:636–643

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Yang H, Song L, Li N, Han QY, Tian C, Gao E, Du J, Xia YL, Li HH (2014) AGGF1 protects from myocardial ischemia/reperfusion injury by regulating myocardial apoptosis and angiogenesis. Apoptosis 19:1254–1268

    Article  PubMed  Google Scholar 

  38. Yu C, Abbott PV (2007) An overview of the dental pulp: its functions and responses to injury. Aust Dent J 52:S4–S16

    Article  PubMed  Google Scholar 

  39. Farges JC, Carrouel F, Keller JF, Baudouin C, Msika P, Bleicher F, Staquet MJ (2011) Cytokine production by human odontoblast-like cells upon Toll-like receptor-2 engagement. Immunobiology 216:513–517

    Article  PubMed  Google Scholar 

  40. Durand SH, Flacher V, Romeas A, Carrouel F, Colomb E, Vincent C, Magloire H, Couble ML, Bleicher F, Staquet MJ, Lebecque S, Farges JC (2006) Lipoteichoic acid increases TLR and functional chemokine expression while reducing dentin formation in in vitro differentiated human odontoblasts. J Immunol 176:2880–2887

    Article  PubMed  Google Scholar 

  41. Keller JF, Carrouel F, Colomb E, Durand SH, Baudouin C, Msika P, Bleicher F, Vincent C, Staquet MJ, Farges JC (2010) Toll-like receptor 2 activation by lipoteichoic acid induces differential production of pro-inflammatory cytokines in human odontoblasts, dental pulp fibroblasts and immature dendritic cells. Immunobiology 215:53–59

    Article  PubMed  Google Scholar 

  42. Reinders ME, Sho M, Izawa A, Wang P, Mukhopadhyay D, Koss KE, Geehan CS, Luster AD, Sayegh MH, Briscoe DM (2003) Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest 112:1655–1665

    Article  PubMed  PubMed Central  Google Scholar 

  43. Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF (2009) Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci U S A 106:21264–21269

    Article  PubMed  PubMed Central  Google Scholar 

  44. Park C, Lee SY, Kim HJ, Park K, Kim JS, Lee SJ (2010) Synergy of TLR2 and H1R on Cox-2 Activation in Pulpal Cells. J Dent Res 89:180–185

    Article  PubMed  Google Scholar 

  45. Horst OV, Tompkins KA, Coats SR, Braham PH, Darveau RP, Dale BA (2009) TGF-beta1 Inhibits TLR-mediated odontoblast responses to oral bacteria. J Dent Res 88:333–338

    Article  PubMed  PubMed Central  Google Scholar 

  46. Farges JC, Keller JF, Carrouel F, Durand SH, Romeas A, Bleicher F, Lebecque S, Staquet MJ (2009) Odontoblasts in the dental pulp immune response. J Exp Zool B Mol Dev Evol 312b:425–436

    Article  PubMed  Google Scholar 

  47. Kang W, Shang L, Wang T, Liu H, Ge S (2018) Rho-kinase inhibitor Y-27632 downregulates LPS-induced IL-6 and IL-8 production via blocking p38 MAPK and NF-kappaB pathways in human gingival fibroblasts. J Periodontol 89:883–893

    Article  PubMed  Google Scholar 

  48. Yadlapati M, Biguetti C, Cavalla F, Nieves F, Bessey C, Bohluli P, Garlet GP, Letra A, Fakhouri WD, Silva RM (2017) Characterization of a vascular endothelial growth factor-loaded bioresorbable delivery system for pulp regeneration. J Endod 43:77–83

    Article  PubMed  Google Scholar 

  49. Zhang Z, Nor F, Oh M, Cucco C, Shi S, Nor JE (2016) Wnt/beta-catenin signaling determines the vasculogenic fate of postnatal mesenchymal stem cells. Stem Cells 34:1576–1587

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tran-Hung L, Mathieu S, About I (2006) Role of human pulp fibroblasts in angiogenesis. J Dent Res 85:819–823

    Article  PubMed  Google Scholar 

  51. Takeuchi N, Hayashi Y, Murakami M, Alvarez FJ, Horibe H, Iohara K, Nakata K, Nakamura H, Nakashima M (2015) Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony stimulating factor. Oral Dis 21:113–122

    Article  PubMed  Google Scholar 

  52. Li L, Chen D, Li J, Wang X, Wang N, Xu C, Wang QK (2014) Aggf1 acts at the top of the genetic regulatory hierarchy in specification of hemangioblasts in zebrafish. Blood 123:501–508

    Article  PubMed  PubMed Central  Google Scholar 

  53. Zhou B, Ma R, Si W, Li S, Xu Y, Tu X, Wang Q (2013) MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Lett 333:159–169

    Article  PubMed  Google Scholar 

  54. Lu Q, Yao Y, Yao Y, Liu S, Huang Y, Lu S, Bai Y, Zhou B, Xu Y, Li L, Wang N, Wang L, Zhang J, Cheng X, Qin G, Ma W, Xu C, Tu X, Wang Q (2012) Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model. PLoS One 7:e46998

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang T, Yao Y, Wang J, Li Y, He P, Pasupuleti V, Hu Z, Jia X, Song Q, Tian XL, Hu C, Chen Q, Wang QK (2016) Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin. Hum Mol Genet 25:5094–5110

    PubMed  PubMed Central  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China (No. 81670993 and 81873716) and The Construction Engineering Special Fund of “Taishan Scholars” of Shandong Province (No. ts20190975). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that no financial or other potential competing interests exist with regard to this study.

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Authors and Affiliations

  1. Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, 250012, Jinan, People’s Republic of China

    Song Shen, Lingling Shang, Hongrui Liu, Qianyu Liang, Wei Liang & Shaohua Ge

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  1. Song Shen
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  2. Lingling Shang
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  3. Hongrui Liu
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  4. Qianyu Liang
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  6. Shaohua Ge
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Correspondence to Shaohua Ge.

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Ethics approval was gained from the Medical Ethical Committee of School of Stomatology, Shandong University (Protocol Number: GR201801).

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Shen, S., Shang, L., Liu, H. et al. AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells. Clin Oral Invest 25, 581–592 (2021). https://doi.org/10.1007/s00784-020-03498-9

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  • DOI: https://doi.org/10.1007/s00784-020-03498-9

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