Cannabinoid type-2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL-1β stimulated primary human periodontal ligament fibroblasts.
CB2 receptor
MAPKs
chemokine
cytokine
periodontal disease
Journal
Journal of periodontal research
ISSN: 1600-0765
Titre abrégé: J Periodontal Res
Pays: United States
ID NLM: 0055107
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
20
08
2019
revised:
08
04
2020
accepted:
24
04
2020
pubmed:
21
6
2020
medline:
15
12
2020
entrez:
21
6
2020
Statut:
ppublish
Résumé
The aim of this study is to understand the role of cannabinoid type 2 receptor (CB2R) during periodontal inflammation and to identify anti-inflammatory agents for the development of drugs to treat periodontitis (PD). Cannabinoid type 2 receptor is found in periodontal tissue at sites of inflammation/infection. Our previous study demonstrated anti-inflammatory responses in human periodontal ligament fibroblasts (hPDLFs) via CB2R ligands. Anandamide (AEA), HU-308 (agonist), and SMM-189 (inverse agonist) were tested for effects on IL-1β-stimulated cytokines, chemokines, and angiogenic and vascular markers expressed by hPDLFs using Mesoscale Discovery V-Plex Kits. Signal transduction pathways (p-c-Jun, p-ERK, p-p-38, p-JNK, p-CREB, and p-NF-kB) were investigated using Cisbio HTRF kits. ACTOne and Tango™ -BLA functional assays were used to measure cyclic AMP (cAMP) and β-arrestin activity. IL-1β stimulated hPDLF production of 18/39 analytes, which were downregulated by the CB2R agonist and the inverse agonist. AEA exhibited pro-inflammatory and anti-inflammatory effects. IL-1β increased phosphoproteins within the first hour except p-JNK. CB2R ligands attenuated p-p38 and p-NFĸB, but a late rise in p-38 was seen with HU-308. As p-ERK levels declined, a significant increase in p-ERK was observed later in the time course by synthetic CB2R ligands. P-JNK was significantly affected by SMM-189 only, while p-CREB was elevated significantly by CB2R ligands at 180 minutes. HU-308 affected both cAMP and β-arrestin pathway. SMM-189 only stimulated cAMP. The findings that CB2R agonist and inverse agonist may potentially regulate inflammation suggest that development of CB2R therapeutics could improve on current treatments for PD and other oral inflammatory pathologies.
Sections du résumé
OBJECTIVE
OBJECTIVE
The aim of this study is to understand the role of cannabinoid type 2 receptor (CB2R) during periodontal inflammation and to identify anti-inflammatory agents for the development of drugs to treat periodontitis (PD).
BACKGROUND
BACKGROUND
Cannabinoid type 2 receptor is found in periodontal tissue at sites of inflammation/infection. Our previous study demonstrated anti-inflammatory responses in human periodontal ligament fibroblasts (hPDLFs) via CB2R ligands.
METHODS
METHODS
Anandamide (AEA), HU-308 (agonist), and SMM-189 (inverse agonist) were tested for effects on IL-1β-stimulated cytokines, chemokines, and angiogenic and vascular markers expressed by hPDLFs using Mesoscale Discovery V-Plex Kits. Signal transduction pathways (p-c-Jun, p-ERK, p-p-38, p-JNK, p-CREB, and p-NF-kB) were investigated using Cisbio HTRF kits. ACTOne and Tango™ -BLA functional assays were used to measure cyclic AMP (cAMP) and β-arrestin activity.
RESULTS
RESULTS
IL-1β stimulated hPDLF production of 18/39 analytes, which were downregulated by the CB2R agonist and the inverse agonist. AEA exhibited pro-inflammatory and anti-inflammatory effects. IL-1β increased phosphoproteins within the first hour except p-JNK. CB2R ligands attenuated p-p38 and p-NFĸB, but a late rise in p-38 was seen with HU-308. As p-ERK levels declined, a significant increase in p-ERK was observed later in the time course by synthetic CB2R ligands. P-JNK was significantly affected by SMM-189 only, while p-CREB was elevated significantly by CB2R ligands at 180 minutes. HU-308 affected both cAMP and β-arrestin pathway. SMM-189 only stimulated cAMP.
CONCLUSION
CONCLUSIONS
The findings that CB2R agonist and inverse agonist may potentially regulate inflammation suggest that development of CB2R therapeutics could improve on current treatments for PD and other oral inflammatory pathologies.
Substances chimiques
Arachidonic Acids
0
CNR2 protein, human
0
Cannabinoids
0
Endocannabinoids
0
Interleukin-18
0
Polyunsaturated Alkamides
0
Receptor, Cannabinoid, CB2
0
anandamide
UR5G69TJKH
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
762-783Subventions
Organisme : Alumni Endowment Fund, University of Tennessee Health Science Center, Tennessee Dental Association Foundation, College of Dentistry, University of Tennessee Health Science Center
ID : Alumni Endowment Fund
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Kassebaum NJ, Bernabe E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. J Dent Res. 2014;93(11):1045-1053.
Brown LJ, Johns BA, Wall TP. The economics of periodontal diseases. Periodontology 2000. 2002;29:223-234.
Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366(9499):1809-1820.
Kornman KS, Crane A, Wang HY, et al. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol. 1997;24(1):72-77.
Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol. 1996;67(10 Suppl):1041-1049.
Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol. 1994;65(3):260-267.
Genco RJ. Host responses in periodontal diseases: Current concepts. J Periodontol. 1992;63(4 Suppl):338-355.
Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of porphyromonas gingivalis. Periodontology 2000 1999;20:168-238.
Agace W, Hedges S, Andersson U, Andersson J, Ceska M, Svanborg C. Selective cytokine production by epithelial cells following exposure to escherichia coli. Infect Immun. 1993;61(2):602-609.
Reinhardt RA, Masada MP, Kaldahl WB, et al. Gingival fluid il-1 and il-6 levels in refractory periodontitis. J Clin Periodontol. 1993;20(3):225-231.
Yamazaki K, Nakajima T, Gemmell E, Polak B, Seymour GJ, Hara K. Il-4- and il-6-producing cells in human periodontal disease tissue. J Oral Pathol Med. 1994;23(8):347-353.
Jiang Y, Russell TR, Graves DT, Cheng H, Nong SH, Levitz SM. Monocyte chemoattractant protein 1 and interleukin-8 production in mononuclear cells stimulated by oral microorganisms. Infect Immun. 1996;64(11):4450-4455.
Tonetti MS, Imboden MA, Lang NP. Neutrophil migration into the gingival sulcus is associated with transepithelial gradients of interleukin-8 and icam-1. J Periodontol. 1998;69(10):1139-1147.
Tsai CC, Ho YP, Chen CC. Levels of interleukin-1 beta and interleukin-8 in gingival crevicular fluids in adult periodontitis. J Periodontol. 1995;66(10):852-859.
Dickinson BC, Moffatt CE, Hagerty D, et al. Interaction of oral bacteria with gingival epithelial cell multilayers. Mol Oral Microbiol. 2011;26(3):210-220.
Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000 2014;64(1):57-80.
Safkan B, Knuuttila M. Corticosteroid therapy and periodontal disease. J Clin Periodontol. 1984;11(8):515-522.
Waite IM, Saxton CA, Young A, Wagg BJ, Corbett M. The periodontal status of subjects receiving non-steroidal anti-inflammatory drugs. J Periodontal Res. 1981;16(1):100-108.
Feldman RS, Szeto B, Chauncey HH, Goldhaber P. Non-steroidal anti-inflammatory drugs in the reduction of human alveolar bone loss. J Clin Periodontol. 1983;10(2):131-136.
Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (nsaids, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010;24(2):121-132.
Croxford JL, Yamamura T. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005;166(1-2):3-18.
Jean-Gilles L, Braitch M, Latif ML, et al. Effects of pro-inflammatory cytokines on cannabinoid cb1 and cb2 receptors in immune cells. Acta Physiol. 2015;214(1):63-74.
Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003;74(4):486-496.
Nakajima Y, Furuichi Y, Biswas KK, et al. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through nf-kappab pathway inhibition. FEBS Lett. 2006;580(2):613-619.
Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232(1):54-61.
Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid cb1 and cb2 receptors. Mol Pharmacol. 1995;48(3):443-450.
Kreitzer FR, Stella N. The therapeutic potential of novel cannabinoid receptors. Pharmacol Ther. 2009;122(2):83-96.
Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5(5):400-411.
Kozono S, Matsuyama T, Biwasa KK, et al. Involvement of the endocannabinoid system in periodontal healing. Biochem Biophys Res Commun. 2010;394(4):928-933.
Han S, Thatte J, Buzard DJ, Jones RM. Therapeutic utility of cannabinoid receptor type 2 (cb(2)) selective agonists. J Med Chem. 2013;56(21):8224-8256.
Abidi AH, Presley CS, Dabbous M, Tipton DA, Mustafa SM, Moore Ii BM. Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hpdl fibroblasts. Arch. Oral Biol. 2018;87:79-85.
Beertsen W, McCulloch CA, Sodek J. The periodontal ligament: A unique, multifunctional connective tissue. Periodontology 2000. 1997;13:20-40.
El-Awady AR, Messer RL, Gamal AY, Sharawy MM, Wenger KH, Lapp CA. Periodontal ligament fibroblasts sustain destructive immune modulators of chronic periodontitis. J Periodontol. 2010;81(9):1324-1335.
Jonsson D, Nebel D, Bratthall G, Nilsson BO. The human periodontal ligament cell: A fibroblast-like cell acting as an immune cell. J Periodontal Res. 2011;46(2):153-157.
Presley C, Abidi A, Suryawanshi S, Mustafa S, Meibohm B, Moore BM. Preclinical evaluation of smm-189, a cannabinoid receptor 2-specific inverse agonist. Pharmacol Res Perspect. 2015;3(4):e00159.
Acuner Ozbabacan SE, Gursoy A, Nussinov R, Keskin O. The structural pathway of interleukin 1 (il-1) initiated signaling reveals mechanisms of oncogenic mutations and snps in inflammation and cancer. PLoS Comput Biol. 2014;10(2):e1003470.
Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor cb2 in immune regulation: Therapeutic prospects for neuroinflammation. Expert Rev Mol Med. 2009;11:e3.
Choi IY, Ju C, Anthony Jalin AM, Lee DI, Prather PL, Kim WK. Activation of cannabinoid cb2 receptor-mediated ampk/creb pathway reduces cerebral ischemic injury. Am J Pathol. 2013;182(3):928-939.
Fujii M, Sherchan P, Soejima Y, et al. Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated creb-bcl-2 pathway after subarachnoid hemorrhage in rats. Exp Neurol. 2014;261:396-403.
Bu W, Ren H, Deng Y, et al. Mild traumatic brain injury produces neuron loss that can be rescued by modulating microglial activation using a cb2 receptor inverse agonist. Front Neurosci. 2016;10:449.
Dhopeshwarkar A, Mackie K. Functional selectivity of cb2 cannabinoid receptor ligands at a canonical and noncanonical pathway. J Pharmacol Exp Ther. 2016;358(2):342-351.
Hanus L, Breuer A, Tchilibon S, et al. Hu-308: A specific agonist for cb(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA. 1999;96(25):14228-14233.
Soethoudt M, Grether U, Fingerle J, et al. Cannabinoid cb2 receptor ligand profiling reveals biased signalling and off-target activity. Nat Commun. 2017;8:13958.
Sanchez GA, Miozza VA, Delgado A, Busch L. Salivary il-1beta and pge2 as biomarkers of periodontal status, before and after periodontal treatment. J Clin Periodontol. 2013;40(12):1112-1117.
Kaushik R, Yeltiwar RK, Pushpanshu K. Salivary interleukin-1beta levels in patients with chronic periodontitis before and after periodontal phase i therapy and healthy controls: A case-control study. J Periodontol. 2011;82(9):1353-1359.
Noh MK, Jung M, Kim SH, et al. Assessment of il-6, il-8 and tnf-α levels in the gingival tissue of patients with periodontitis. Exp Ther Med. 2013;6(3):847-851.
Beklen A, Ainola M, Hukkanen M, Gurgan C, Sorsa T, Konttinen YT. Mmps, il-1, and tnf are regulated by il-17 in periodontitis. J Dent Res. 2007;86(4):347-351.
Hanazawa S, Kawata Y, Takeshita A, et al. Expression of monocyte chemoattractant protein 1 (mcp-1) in adult periodontal disease: Increased monocyte chemotactic activity in crevicular fluids and induction of mcp-1 expression in gingival tissues. Infect Immun. 1993;61(12):5219-5224.
Takahashi K, Takashiba S, Nagai A, et al. Assessment of interleukin-6 in the pathogenesis of periodontal disease. J Periodontol. 1994;65(2):147-153.
Shi Y, Liu CH, Roberts AI, et al. Granulocyte-macrophage colony-stimulating factor (gm-csf) and t-cell responses: What we do and don't know. Cell Res 2006;16(2):126-133.
Gamonal J, Sanz M, O'Connor A, et al. Delayed neutrophil apoptosis in chronic periodontitis patients. J Clin Periodontol. 2003;30(7):616-623.
Rubio-Perez JM, Morillas-Ruiz JM. A review: Inflammatory process in alzheimer's disease, role of cytokines. The Scientific World Journal. 2012;2012:15.
Apostolakis S, Vogiatzi K, Amanatidou V, Spandidos DA. Interleukin 8 and cardiovascular disease. Cardiovasc Res. 2009;84(3):353-360.
Gamonal J, Acevedo A, Bascones A, Jorge O, Silva A. Levels of interleukin-1β, -8, and -10 and rantes in gingival crevicular fluid and cell populations in adult periodontitis patients and the effect of periodontal treatment. J Periodontol. 2000;71(10):1535-1545.
Fujita T, Shiba H, Kurihara H. Irsogladine maleate regulates barrier function and neutrophil accumulation in the gingival epithelium. J Oral Biosci. 2012;54(2):79-82.
Booth V, Young S, Cruchley A, Taichman NS, Paleolog E. Vascular endothelial growth factor in human periodontal disease. J Periodontal Res. 1998;33(8):491-499.
Prapulla DV, Sujatha PB, Pradeep AR. Gingival crevicular fluid vegf levels in periodontal health and disease. J Periodontol. 2007;78(9):1783-1787.
Kim S-K, Park S-G, Kim K-W. Expression of vascular endothelial growth factor in oral squamous cell carcinoma. J Korean Assoc Oral Maxillofac Surg. 2015;41(1):11-18.
Vestweber D, Blanks JE. Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev. 1999;79(1):181-213.
Hosokawa Y, Hosokawa I, Ozaki K, Nakae H, Matsuo T. Cytokines differentially regulate icam-1 and vcam-1 expression on human gingival fibroblasts. Clin Exp Immunol. 2006;144(3):494-502.
Lappin DF, McGregor AM, Kinane DF. The systemic immune response is more prominent than the mucosal immune response in the pathogenesis of periodontal disease. J Clin Periodontol. 2003;30(9):778-786.
Mole N, Kennel-de March A, Martin G, Miller N, Bene MC, Faure GC. High levels of soluble intercellular adhesion molecule-1 (icam-1) in crevicular fluid of periodontitis patients with plaque. J Clin Periodontol. 1998;25(9):754-758.
Liu J, Wang Y, Ouyang X. Beyond toll-like receptors: Porphyromonas gingivalis induces il-6, il-8, and vcam-1 expression through nod-mediated nf-kappab and erk signaling pathways in periodontal fibroblasts. Inflammation. 2014;37(2):522-533.
Golz L, Memmert S, Rath-Deschner B, et al. Hypoxia and p. Gingivalis synergistically induce hif-1 and nf-kappab activation in pdl cells and periodontal diseases. Mediators Inflamm. 2015;2015:438085.
Liu J, Duan J, Wang Y, Ouyang X. Intracellular adhesion molecule-1 is regulated by porphyromonas gingivalis through nucleotide binding oligomerization domain-containing proteins 1 and 2 molecules in periodontal fibroblasts. J Periodontol. 2014;85(2):358-368.
Suzuki T, Sugita N, Yoshie H, Hara K. Presence of activated eosinophils, high ige and scd23 titers in gingival crevicular fluid of patients with adult periodontitis. J Periodontal Res. 1995;30(3):159-166.
Feder LS, Stelts D, Chapman RW, et al. Role of nitric oxide on eosinophilic lung inflammation in allergic mice. Am J Respir Cell Mol Biol. 1997;17(4):436-442.
Ferreira HH, Bevilacqua E, Gagioti SM, et al. Nitric oxide modulates eosinophil infiltration in antigen-induced airway inflammation in rats. Eur J Pharmacol. 1998;358(3):253-259.
Shinkai A, Yoshisue H, Koike M, et al. A novel human cc chemokine, eotaxin-3, which is expressed in il-4-stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. J Immunol. 1999;163(3):1602-1610.
Ribas D, Fernandez-Carranco MC, Hajji N, Bobadilla P, Monteseirin J. Eosinophil cationic protein and histamine production by neutrophils from patients with periodontitis. J Periodontol. 2018;89(2):228-234.
Navarro S, Aleu J, Jiménez M, Boix E, Cuchillo CM, Nogués MV. The cytotoxicity of eosinophil cationic protein/ribonuclease 3 on eukaryotic cell lines takes place through its aggregation on the cell membrane. Cell Mol Life Sci. 2008;65(2):324-337.
Nisha KJ, Suresh A, Anilkumar A, Padmanabhan S. Mip-1α and mcp-1 as salivary biomarkers in periodontal disease. Saudi Dental J. 2018;30(4):292-298.
Kabashima H, Yoneda M, Nagata K, Hirofuji T, Maeda K. The presence of chemokine (mcp-1, mip-1alpha, mip-1beta, ip-10, rantes)-positive cells and chemokine receptor (ccr5, cxcr3)-positive cells in inflamed human gingival tissues. Cytokine. 2002;20(2):70-77.
Dutzan N, Vernal R, Hernandez M, et al. Levels of interferon-gamma and transcription factor t-bet in progressive periodontal lesions in patients with chronic periodontitis. J Periodontol. 2009;80(2):290-296.
Aldahlawi S, Youssef AR, Shahabuddin S. Evaluation of chemokine cxcl10 in human gingival crevicular fluid, saliva, and serum as periodontitis biomarker. J Inflamm Res. 2018;11:389-396.
McFarlane CG, Meikle MC. Interleukin-2, interleukin-2 receptor and interleukin-4 levels are elevated in the sera of patients with periodontal disease. J Periodontal Res. 1991;26(5):402-408.
Tâlvan ETMC, Chisnoiu D, Cristea V, Câmpian RS Expression of interleukin (il)-1β, il-8, il-10 and il-13 in chronic adult periodontitis progression. Archives Med 2017;9(3:4).
Zhang W, Xu P, Chen Z, Cheng Y, Li X, Mao Q. Il-13 -1112 polymorphism and periodontitis susceptibility: A meta-analysis. BMC Oral Health. 2018;18(1):21-21.
Hashimoto S, Gon Y, Takeshita I, Maruoka S, Horie T. Il-4 and il-13 induce myofibroblastic phenotype of human lung fibroblasts through c-jun nh2-terminal kinase-dependent pathway. J Allergy Clin Immunol. 2001;107(6):1001-1008.
Hosokawa Y, Hosokawa I, Ozaki K, Nakae H, Matsuo T. Cc chemokine ligand 17 in periodontal diseases: Expression in diseased tissues and production by human gingival fibroblasts. J Periodontal Res. 2008;43(4):471-477.
Alvarez C, Rojas C, Rojas L, Cafferata EA, Monasterio G, Vernal R. Regulatory t lymphocytes in periodontitis: A translational view. Mediators Inflamm. 2018;2018:7806912.
Garlisi CG, Xiao H, Tian F, et al. The assignment of chemokine-chemokine receptor pairs: Tarc and mip-1 beta are not ligands for human cc-chemokine receptor 8. Eur J Immunol. 1999;29(10):3210-3215.
Panina-Bordignon P, Papi A, Mariani M, et al. The c-c chemokine receptors ccr4 and ccr8 identify airway t cells of allergen-challenged atopic asthmatics. J Clin Invest. 2001;107(11):1357-1364.
Dinarello CA. Proinflammatory cytokines. Chest. 2000;118(2):503-508.
Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400(6743):452-457.
Ryberg E, Larsson N, Sjögren S, et al. The orphan receptor gpr55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092-1101.
Sharir H, Console-Bram L, Mundy C, Popoff SN, Kapur A, Abood ME. The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor gpr55. J Neuroimmune Pharmacol. 2012;7(4):856-865.
McHugh D, Page J, Dunn E, Bradshaw HB. Δ(9) -tetrahydrocannabinol and n-arachidonyl glycine are full agonists at gpr18 receptors and induce migration in human endometrial hec-1b cells. Br J Pharmacol. 2012;165(8):2414-2424.
Ross RA. Anandamide and vanilloid trpv1 receptors. Br J Pharmacol. 2003;140(5):790-801.
Haruta C. effects of anandamide on il-11 production through the trpv1 of human periodontal ligament cells. Kokubyo Gakkai Zasshi. 2012;79(1):7-14.
O'Sullivan SE. An update on ppar activation by cannabinoids. Br J Pharmacol. 2016;173(12):1899-1910.
Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P. Anandamide induced ppargamma transcriptional activation and 3t3-l1 preadipocyte differentiation. Eur J Pharmacol. 2005;517(3):174-181.
Son GY, Hong JH, Chang I, Shin DM. Induction of il-6 and il-8 by activation of thermosensitive trp channels in human pdl cells. Arch Oral Biol. 2015;60(4):526-532.
Partovi M, Sadeghein A, Azizi E, Ostad SN. Mitogenic effect of l-dopa on human periodontal ligament fibroblast cells. J Endod. 2002;28(3):193-196.
Zhao B, Hu M, Wu H, et al. Peroxisome proliferator-activated receptor-γ and its related pathway in bone marrow mesenchymal stem cell differentiation co-cultured with mechanically stretched ligament fibroblasts. Int J Mol Med. 2018;42(1):219-227.
Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P. Direct inhibition of t-type calcium channels by the endogenous cannabinoid anandamide. EMBO J. 2001;20(24):7033-7040.
Feng DF, Wang CY, Wang H, Wang J, Zhang MM, Jiao XH. Bfgf-induced human periodontal ligament fibroblasts proliferation through t-type voltage-dependent calcium channels. Acta Odontol Scand. 2013;71(1):9-14.
Maingret F, Patel AJ, Lazdunski M, Honoré E. The endocannabinoid anandamide is a direct and selective blocker of the background k(+) channel task-1. EMBO J. 2001;20(1-2):47-54.
Yamamoto T, Ohara A, Nishikawa M, Yamamoto G, Saeki Y. Dexamethasone-induced up-regulation of two-pore domain k+ channel genes, task-1 and twik-2, in cultured human periodontal ligament fibroblasts. In Vitro Cell Dev Biol Anim. 2011;47(4):273-279.
Kendall AC, Pilkington SM, Sassano G, Rhodes LE, Nicolaou A. N-acyl ethanolamide and eicosanoid involvement in irritant dermatitis. Br J Dermatol. 2016;175(1):163-171.
Nakajima Y, Furuichi Y, Biswas KK, et al. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through nf-κb pathway inhibition. FEBS Lett. 2006;580(2):613-619.
Ozdemir B, Shi B, Bantleon HP, Moritz A, Rausch-Fan X, Andrukhov O. Endocannabinoids and inflammatory response in periodontal ligament cells. PLoS ONE. 2014;9(9):e107407.
Pan W, Wang Q, Chen Q. The cytokine network involved in the host immune response to periodontitis. Int J Oral Sci. 2019;11(3):30.
Qian H, Yi J, Zhou J, et al. Activation of cannabinoid receptor cb2 regulates lps-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in human periodontal ligament cells. Open J Stomatol. 2013;3:44-51.
Brach MA, de Vos S, Gruss HJ, Herrmann F. Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death. Blood. 1992;80(11):2920-2924.
Cox G, Gauldie J, Jordana M. Bronchial epithelial cell-derived cytokines (g-csf and gm-csf) promote the survival of peripheral blood neutrophils in vitro. Am J Respir Cell Mol Biol. 1992;7(5):507-513.
Yong KL, Linch DC. Differential effects of granulocyte- and granulocyte-macrophage colony-stimulating factors (g- and gm-csf) on neutrophil adhesion in vitro and in vivo. Eur J Haematol. 1992;49(5):251-259.
Becher B, Tugues S, Greter M. Gm-csf: From growth factor to central mediator of tissue inflammation. Immunity. 2016;45(5):963-973.
Montecucco F, Burger F, Mach F, Steffens S. Cb2 cannabinoid receptor agonist jwh-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294(3):H1145-1155.
Merighi S, Gessi S, Varani K, et al. Cannabinoid cb2 receptors modulate erk-1/2 kinase signalling and no release in microglial cells stimulated with bacterial lipopolysaccharide. Br J Pharmacol. 2012;165(6):1773-1788.
Ofek O, Attar-Namdar M, Kram V, et al. Cb2 cannabinoid receptor targets mitogenic gi protein-cyclin d1 axis in osteoblasts. J Bone Miner Res. 2011;26(2):308-316.
Cabral GA, Griffin-Thomas L. Emerging role of the cb(2) cannabinoid receptor in immune regulation and therapeutic prospects. Expert Rev Mol Med. 2009;11:e3-e3.
Gupta M, Chaturvedi R, Jain A. Role of monocyte chemoattractant protein-1 (mcp-1) as an immune-diagnostic biomarker in the pathogenesis of chronic periodontal disease. Cytokine. 2013;61(3):892-897.
Yu X, Graves DT. Fibroblasts, mononuclear phagocytes, and endothelial cells express monocyte chemoattractant protein-1 (mcp-1) in inflamed human gingiva. J Periodontol. 1995;66(1):80-88.
Kabashima H, Yoneda M, Nagata K, Hirofuji T, Maeda K. The presence of chemokine (mcp-1, mip-1α, mip-1β, ip-10, rantes)-positive cells and chemokine receptor (ccr5, cxcr3)-positive cells in inflamed human gingival tissues. Cytokine. 2002;20(2):70-77.
Gui H, Liu X, Wang Z-W, He D-Y, Su D-F, Dai S-M. Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis. Rheumatology. 2014;53(5):802-809.
Faubert Kaplan BL, Kaminski NE. Cannabinoids inhibit the activation of erk mapk in pma/io-stimulated mouse splenocytes. Int Immunopharmacol. 2003;3(10):1503-1510.
Kozono S, Matsuyama T, Biwasa KK, et al. Involvement of the endocannabinoid system in periodontal healing. Biochem Biophys Res Comm. 2010;394(4):928-933.
Montecucco F, Burger F, Mach F, Steffens S. Cb2 cannabinoid receptor agonist jwh-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294(3):H1145-H1155.
Correa F, Docagne F, Mestre L, et al. A role for cb2 receptors in anandamide signalling pathways involved in the regulation of il-12 and il-23 in microglial cells. Biochem Pharmacol. 2009;77(1):86-100.
Correa F, Hernangomez M, Mestre L, et al. Anandamide enhances il-10 production in activated microglia by targeting cb(2) receptors: Roles of erk1/2, jnk, and nf-kappab. Glia. 2010;58(2):135-147.
Wang J, Xu J, Peng Y, et al. Phosphorylation of extracellular signal-regulated kinase as a biomarker for cannabinoid receptor 2 activation. Heliyon. 2018;4(11):e00909.
Hytti M, Andjelic S, Josifovska N, et al. Cb2 receptor activation causes an erk1/2-dependent inflammatory response in human rpe cells. Sci Rep. 2017;7(1):16169.
Kanaya S, Xiao B, Sakisaka Y, et al. Extracellular calcium increases fibroblast growth factor 2 gene expression via extracellular signal-regulated kinase 1/2 and protein kinase a signaling in mouse dental papilla cells. J Appl Oral Sci. 2018;26:e20170231.
Briaud I, Lingohr MK, Dickson LM, Wrede CE, Rhodes CJ. Differential activation mechanisms of erk-1/2 and p70<sup>s6k</sup> by glucose in pancreatic β-cells. Diabetes. 2003;52(4):974-983.
Belcheva MM, Coscia CJ. Diversity of g protein-coupled receptor signaling pathways to erk/map kinase. Neurosignals. 2002;11(1):34-44.
Maeng Y-S, Min J-K, Kim JH, et al. Erk is an anti-inflammatory signal that suppresses expression of nf-κb-dependent inflammatory genes by inhibiting ikk activity in endothelial cells. Cell Signal. 2006;18(7):994-1005.
Xiao YQ, Malcolm K, Worthen GS, et al. Cross-talk between erk and p38 mapk mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-beta. J Biol Chem. 2002;277(17):14884-14893.
Rämet M, Lanot R, Zachary D, Manfruelli P. Jnk signaling pathway is required for efficient wound healing in drosophila. Dev Biol. 2002;241(1):145-156.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314.
Javelaud D, Laboureau J, Gabison E, Verrecchia F, Mauviel A. Disruption of basal jnk activity differentially affects key fibroblast functions important for wound healing. J Biol Chem. 2003;278(27):24624-24628.
Basso FG, Pansani TN, Turrioni AP, Soares DG, de Souza Costa CA, Hebling J. Tumor necrosis factor-alpha and interleukin (il)-1beta, il-6, and il-8 impair in vitro migration and induce apoptosis of gingival fibroblasts and epithelial cells, delaying wound healing. J Periodontol. 2016;87(8):990-996.