A critique on nuclear factor-kappa B and signal transducer and activator of transcription 3: The key transcription factors in periodontal pathogenesis

Ranjith Ambili, Presanthila Janam, Ranjith Ambili, Presanthila Janam

Abstract

Periodontal disease is initiated by microorganisms in dental plaque, and host immunoinflammatory response to the microbial challenge helps in disease progression. Conventional periodontal therapy was mainly targeted on the elimination of microbial component. However, a better understanding of molecular aspects in host response will enable the clinicians to formulate effective host modulation therapy (HMT) for the periodontal management. Inflammatory mediators were the main targets for HMT in the past. Transcription factors can regulate the production of multiple mediators simultaneously, and inhibition of these factors will be more beneficial than blocking individual molecule. Two important transcription factors implicated in chronic inflammatory diseases are nuclear factor kappa B (NF-κB) and signal transducers and activators of transcription 3. The role of these factors in periodontal disease is a less explored area. This comprehensive review is aimed at unveiling the critical role of NF-κB and signal transducers and activators of transcription 3 in periodontal pathogenesis. An online search was performed using MEDLINE/PubMed database. All publications till 2016 related to NF-κB, signal transducer and activator of transcription 3 (STAT3), and inflammation were included in writing this review. A total of 27,390 references were published based on the search terms used. Out of these, 507 were related to the periodontal research published in English till 2016. Relevant papers were chosen after carefully reading the abstract. This review has attempted to comprehend the existing knowledge regarding the role of transcription factors NF-κB and STAT3 in periodontal disease. Moreover, it also provides a connecting molecular link for the periodontal medicine concept.

Keywords: Host response; Signal Transducer and Activator of Transcription 3; inflammation; nuclear factor kappa B; periodontal disease; transcription factors.

Conflict of interest statement

There are no conflicts of interest.

Figures

Figure 1
Figure 1
Activation of nuclear factor kappa B and signal transducer and activator of transcription 3 and possible cross talk (indicated by dotted red arrow) in their signaling in periodontal disease. TLR – Toll like receptors, LPS – Lipopolysaccharide, JAK – Janus activated kinase, STAT3 – Signal signal transducer and activator of transcription 3, MYD88 – Myeloid differentiation primary response 88, IXB – its not X but kappa (κ)- the expansion is inhibitor kappa B, P50 – PROTEIN 50, P65 – PROTEIN 65, NFB – nuclear factor-kappa B

References

    1. Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000. 2014;64:57–80.
    1. Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: Keystones, pathobionts, and host response. Trends Immunol. 2014;35:3–11.
    1. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappa B by a posttranslational mechanism. Cell. 1986;47:921–8.
    1. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu Rev Immunol. 1996;14:649–83.
    1. Akira S. Functional roles of STAT family proteins: Lessons from knockout mice. Stem Cells. 1999;17:138–46.
    1. Zhong Z, Wen Z, Darnell JE Jr. Stat3 and stat4: Members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994;91:4806–10.
    1. Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–50.
    1. Huang S. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: Clinical implications. Clin Cancer Res. 2007;13:1362–6.
    1. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21:11–9.
    1. Cha B, Lim JW, Kim H. Jak1/Stat3 is an upstream signaling of NF-κB activation in Helicobacter pylori-induced IL-8 production in gastric epithelial AGS cells. Yonsei Med J. 2015;56:862–6.
    1. Greenhill CJ, Rose-John S, Lissilaa R, Ferlin W, Ernst M, Hertzog PJ, et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol. 2011;186:1199–208.
    1. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66.
    1. Watanabe A, Takeshita A, Kitano S, Hanazawa S. CD14-mediated signal pathway of Porphyromonas gingivalis lipopolysaccharide in human gingival fibroblasts. Infect Immun. 1996;64:4488–94.
    1. Gölz L, Memmert S, Rath-Deschner B, Jäger A, Appel T, Baumgarten G, et al. Hypoxia and P. gingivalis synergistically induce HIF-1 and NF-κB activation in PDL cells and periodontal diseases. Mediators Inflamm. 2015;2015:438085.
    1. Milward MR, Chapple IL, Wright HJ, Millard JL, Matthews JB, Cooper PR, et al. Differential activation of NF-kappaB and gene expression in oral epithelial cells by periodontal pathogens. Clin Exp Immunol. 2007;148:307–24.
    1. Hu P, Huang P, Chen MW. Curcumin attenuates cyclooxygenase-2 expression via inhibition of the NF-κB pathway in lipopolysaccharide-stimulated human gingival fibroblasts. Cell Biol Int. 2013;37:443–8.
    1. Kida Y, Kobayashi M, Suzuki T, Takeshita A, Okamatsu Y, Hanazawa S, et al. Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. Cytokine. 2005;29:159–68.
    1. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol. 1997;17:4015–23.
    1. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–8.
    1. Edwards JR, Mundy GR. Advances in osteoclast biology: Old findings and new insights from mouse models. Nat Rev Rheumatol. 2011;7:235–43.
    1. Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R, et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009;15:682–9.
    1. Chen X, Hu C, Wang G, Li L, Kong X, Ding Y, et al. Nuclear factor-κB modulates osteogenesis of periodontal ligament stem cells through competition with β-catenin signaling in inflammatory microenvironments. Cell Death Dis. 2013;4:e510.
    1. Ambili R, Santhi WS, Janam P, Nandakumar K, Pillai MR. Expression of activated transcription factor nuclear factor-kappaB in periodontally diseased tissues. J Periodontol. 2005;76:1148–53.
    1. Arabaci T, Cicek Y, Canakci V, Canakci CF, Ozgoz M, Albayrak M, et al. Immunohistochemical and stereologic analysis of NF-κB activation in chronic periodontitis. Eur J Dent. 2010;4:454–61.
    1. Jotwani R, Moonga BS, Gupta S, Cutler CW. Nuclear factor-kappaB p50 subunits in chronic periodontitis and Porphyromonas gingivalis lipopolysaccharide-pulsed dendritic cells. Ann N Y Acad Sci. 2010;1192:278–85.
    1. Hosokawa Y, Shindo S, Hosokawa I, Ozaki K, Matsuo T. IL-6 trans-signaling enhances CCL20 production from IL-1β-stimulated human periodontal ligament cells. Inflammation. 2014;37:381–6.
    1. Garcia de Aquino S, Manzolli Leite FR, Stach-Machado DR, Francisco da Silva JA, Spolidorio LC, Rossa C Jr, et al. Signaling pathways associated with the expression of inflammatory mediators activated during the course of two models of experimental periodontitis. Life Sci. 2009;84:745–54.
    1. Chaves de Souza JA, Nogueira AV, Chaves de Souza PP, Kim YJ, Silva Lobo C, Pimentel Lopes de Oliveira GJ, et al. SOCS3 expression correlates with severity of inflammation, expression of proinflammatory cytokines, and activation of STAT3 and p38 MAPK in LPS-induced inflammation in vivo. Mediators Inflamm. 2013;2013:650812.
    1. Romeo G, Liu WH, Asnaghi V, Kern TS, Lorenzi M. Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. Diabetes. 2002;51:2241–8.
    1. Romeo GR, Kazlauskas A. Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1. J Biol Chem. 2008;283:9595–605.
    1. Macha MA, Matta A, Chauhan SS, Siu KW, Ralhan R. Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells. Carcinogenesis. 2011;32:368–80.
    1. Shankar E, Vykhovanets EV, Vykhovanets OV, Maclennan GT, Singh R, Bhaskaran N, et al. High-fat diet activates pro-inflammatory response in the prostate through association of Stat-3 and NF-κB. Prostate. 2012;72:233–43.
    1. Bae WJ, Shin MR, Kang SK, Zhang-Jun, Kim JY, Lee SC, et al. HIF-2 inhibition supresses inflammatory responses and osteoclastic differentiation in human periodontal ligament cells. J Cell Biochem. 2015;116:1241–55.
    1. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, et al. STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol. 2006;176:5652–61.
    1. Cullinan MP, Ford PJ, Seymour GJ. Periodontal disease and systemic health: Current status. Aust Dent J. 2009;54(Suppl 1):S62–9.
    1. Nichols TC, Fischer TH, Deliargyris EN, Baldwin AS Jr. Role of nuclear factor-kappa B (NF-kappa B) in inflammation, periodontitis, and atherogenesis. Ann Periodontol. 2001;6:20–9.
    1. Gharavi NM, Alva JA, Mouillesseaux KP, Lai C, Yeh M, Yeung W, et al. Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J Biol Chem. 2007;282:31460–8.
    1. Li Q, Pan C, Teng D, Lin L, Kou Y, Haase EM, et al. Porphyromonas gingivalis modulates Pseudomonas aeruginosa-induced apoptosis of respiratory epithelial cells through the STAT3 signaling pathway. Microbes Infect. 2014;16:17–27.
    1. Mahendra J, Parthiban PS, Mahendra L, Balakrishnan A, Shanmugam S, Junaid M, et al. Evidence linking the role of placental expressions of peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B in the pathogenesis of preeclampsia associated with periodontitis. J Periodontol. 2016;87:962–70.
    1. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.
    1. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: A magic bullet? Science. 2013;339:286–91.
    1. Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: A prospective cohort study. Lancet Oncol. 2008;9:550–8.
    1. Bollrath J, Greten FR. IKK/NF-kappaB and STAT3 pathways: Central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep. 2009;10:1314–9.
    1. Choi Y, Kim JK, Yoo JY. NFκB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Mol Oncol. 2014;8:642–55.
    1. Li N, Grivennikov SI, Karin M. The unholy trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011;19:429–31.
    1. Binder Gallimidi A, Fischman S, Revach B, Bulvik R, Maliutina A, Rubinstein AM, et al. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget. 2015;6:22613–23.
    1. Mbalaviele G, Anderson G, Jones A, De Ciechi P, Settle S, Mnich S, et al. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther. 2006;317:1044–53.
    1. Rogers JE, Li F, Coatney DD, Otremba J, Kriegl JM, Protter TA, et al. A p38 mitogen-activated protein kinase inhibitor arrests active alveolar bone loss in a rat periodontitis model. J Periodontol. 2007;78:1992–8.
    1. Souza JA, Rossa C, Jr, Garlet GP, Nogueira AV, Cirelli JA. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease. J Appl Oral Sci. 2012;20:128–38.
    1. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: Balancing life and death – A new approach to cancer therapy. J Clin Invest. 2005;115:2625–32.
    1. Shimizu H, Nakagami H, Morita S, Tsukamoto I, Osako MK, Nakagami F, et al. New treatment of periodontal diseases by using NF-kappaB decoy oligodeoxynucleotides via prevention of bone resorption and promotion of wound healing. Antioxid Redox Signal. 2009;11:2065–75.
    1. Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487–97.
    1. Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60:1895–905.
    1. West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs. 2009;10:491–504.
    1. Kortylewski M, Swiderski P, Herrmann A, Wang L, Kowolik C, Kujawski M, et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol. 2009;27:925–32.
    1. Nowell MA, Williams AS, Carty SA, Scheller J, Hayes AJ, Jones GW, et al. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol. 2009;182:613–22.
    1. Liu W, Oseroff AR, Baumann H. Photodynamic therapy causes cross-linking of signal transducer and activator of transcription proteins and attenuation of interleukin-6 cytokine responsiveness in epithelial cells. Cancer Res. 2004;64:6579–87.
    1. Samavati L, Rastogi R, Du W, Hüttemann M, Fite A, Franchi L, et al. STAT3 tyrosine phosphorylation is critical for interleukin 1 beta and interleukin-6 production in response to lipopolysaccharide and live bacteria. Mol Immunol. 2009;46:1867–77.
    1. Saravanan S, Islam VI, Babu NP, Pandikumar P, Thirugnanasambantham K, Chellappandian M, et al. Swertiamarin attenuates inflammation mediators via modulating NF-κB/I κB and JAK2/STAT3 transcription factors in adjuvant induced arthritis. Eur J Pharm Sci. 2014;56:70–86.
    1. Wang Q, Li H, Xie H, Fu M, Guo B, Ding Y, et al. 25-hydroxyvitamin D3 attenuates experimental periodontitis through downregulation of TLR4 and JAK1/STAT3 signaling in diabetic mice. J Steroid Biochem Mol Biol. 2013;135:43–50.
    1. Yang DJ, Chang YY, Lin HW, Chen YC, Hsu SH, Lin JT, et al. Inhibitory effect of litchi (Litchi chinensis sonn.) flower on lipopolysaccharide-induced expression of proinflammatory mediators in RAW2647 cells through NF-κB, ERK, and JAK2/STAT3 inactivation. J Agric Food Chem. 2014;62:3458–65.
    1. Monk JM, Liddle DM, De Boer AA, Brown MJ, Power KA, Ma DW, et al. Fish-oil-derived n-3 PUFAs reduce inflammatory and chemotactic adipokine-mediated cross-talk between co-cultured murine splenic CD8+T cells and adipocytes. J Nutr. 2015;145:829–38.

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