Int J Stomatol ›› 2023, Vol. 50 ›› Issue (3): 329-334.doi: 10.7518/gjkq.2023030

• Reviews • Previous Articles     Next Articles

Research progress on the role of interleukin-6-hepcidin signal axis in regulating the pathogenesis of periodontitis-associated anemia

Sun Jia1(),Han Ye2,Hou Jianxia2()   

  1. 1.Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China
    2.Dept. of Periodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Cli-nical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing 100081, China
  • Received:2022-10-05 Revised:2023-01-02 Online:2023-05-01 Published:2023-05-16
  • Contact: Jianxia Hou;
  • Supported by:
    National Natural Science Foundation of China(82071117);Natural Science Foundation of Beijing(7212136);Health Science and Technology Project of Tianjin(TJWJ2022QN073)


Periodontitis is a chronic inflammatory disease initiated by bacterial infection. The pathogenic micro-organisms and their toxic products activate the host defense system and evoke immune-inflammatory responses, which affect systemic health. Periodontitis is a risk factor for many systemic diseases. Anemia of inflammation (AI), the second most prevalent type of anemia, occurs in chronic or acute infections and manifests as infection, inflammation, or tumor. These diseases activate the host defense system, resulting in systemic iron disorder and iron-restricted hemoglobin production disorders. A close association exists between AI and periodontitis, but the potential mechanism remains unclear. The interleukin-6-hepcidin signal axis is suggested to play a central role. This paper discusses the recent findings of the asso-ciation between AI and periodontitis to provide theoretical basis and clinical guidance for the prevention, diagnosis, and treatment of periodontitis-associated AI.

Key words: periodontitis, anemia of inflammation, iron metabolism, hepcidin, interleukin-6

CLC Number: 

  • R 781.4

1 Slots J. Periodontitis: facts, fallacies and the future[J]. Periodontol 2000, 2017, 75(1): 7-23.
2 Sanz M, del Castillo AM, Jepsen S, et al. Periodontitis and cardiovascular diseases. Consensus report[J]. Glob Heart, 2020, 15(1): 1.
3 Baeza M, Morales A, Cisterna C, et al. Effect of periodontal treatment in patients with periodontitis and diabetes: systematic review and meta-analysis[J]. J Appl Oral Sci, 2020, 28: e20190248.
4 Bartold PM, Lopez-Oliva I. Periodontitis and rheumatoid arthritis: an update 2012-2017[J]. Periodontol 2000, 2020, 83(1): 189-212.
5 Pritchard AB, Crean S, Olsen I, et al. Periodontitis, microbiomes and their role in Alzheimer’s disease[J]. Front Aging Neurosci, 2017, 9: 336.
6 Hutter JW, van der Velden U, Varoufaki A, et al. Lower numbers of erythrocytes and lower levels of hemoglobin in periodontitis patients compared to control subjects[J]. J Clin Periodontol, 2001, 28(10): 930-936.
7 Naik V, Acharya A, Deshmukh VL, et al. Genera-lized, severe, chronic periodontitis is associated with anemia of chronic disease: a pilot study in urban, In-dian males[J]. J Investig Clin Dent, 2010, 1(2): 139-143.
8 Anand PS, Sagar DK, Ashok S, et al. Association of aggressive periodontitis with reduced erythrocyte counts and reduced hemoglobin levels[J]. J Perio-dontal Res, 2014, 49(6): 719-728.
9 Pradeep AR, Anuj S. Anemia of chronic disease and chronic periodontitis: does periodontal therapy have an effect on anemic status[J]. J Periodontol, 2011, 82(3): 388-394.
10 Malhotra R, Kapoor A, Grover V, et al. Effect of scaling and root planing on erythrocyte count, hemoglobin and hematocrit in patients with chronic perio-dontal disease[J]. J Dent Hyg, 2012, 86(3): 195-203.
11 Wu DL, Lin ZS, Zhang SW, et al. Decreased hemoglobin concentration and iron metabolism disorder in periodontitis: systematic review and meta-analysis[J]. Front Physiol, 2019, 10: 1620.
12 Ganz T. Anemia of inflammation[J]. N Engl J Med, 2019, 381(12): 1148-1157.
13 Weiss G, Ganz T, Goodnough LT. Anemia of inflammation[J]. Blood, 2019, 133(1): 40-50.
14 Nemeth E, Ganz T. Anemia of inflammation[J]. Hematol Oncol Clin North Am, 2014, 28(4): 671-681.
15 Nairz M, Theurl I, Wolf D, et al. Iron deficiency or anemia of inflammation: differential diagnosis and mechanisms of anemia of inflammation[J]. Wien Med Wochenschr, 2016, 166(13/14): 411-423.
16 Muckenthaler MU, Rivella S, Hentze MW, et al. A red carpet for iron metabolism[J]. Cell, 2017, 168(3): 344-361.
17 Saneela S, Iqbal R, Raza A, et al. Hepcidin: a key regulator of iron[J]. J Pak Med Assoc, 2019, 69(8): 1170-1175.
18 Agarwal AK, Yee J. Hepcidin[J]. Adv Chronic Kidney Dis, 2019, 26(4): 298-305.
19 Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus [J]. Blood, 2014, 123(8): 1137-1145.
20 Jelkmann W. Regulation of erythropoietin production[J]. J Physiol, 2011, 589(6): 1251-1258.
21 Felli N, Pedini F, Zeuner A, et al. Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis[J]. J Immunol, 2005, 175(3): 1464-1472.
22 Gokhale SR, Sumanth S, Padhye AM. Evaluation of blood parameters in patients with chronic periodontitis for signs of anemia[J]. J Periodontol, 2010, 81(8): 1202-1206.
23 Khan NS, Luke R, Soman RR, et al. Qualitative assessment of red blood cell parameters for signs of anemia in patients with chronic periodontitis[J]. J Int Soc Prev Community Dent, 2015, 5(6): 476-481.
24 Latha S, Thirugnanamsambandan S, Arun RT, et al. Serum ferritin level and red blood cell parameters in healthy controls and chronic periodontitis patients[J]. J Pharm Bioallied Sci, 2015, 7(): S184-S189.
25 Kolte RA, Kolte AP, Deshpande NM. Assessment and comparison of anemia of chronic disease in healthy subjects and chronic periodontitis patients: a clinical and hematological study[J]. J Indian Soc Periodontol, 2014, 18(2): 183-186.
26 Anumolu VN, Srikanth A, Paidi K. Evaluation of the relation between anemia and periodontitis by estimation of blood parameters: a cross-sectional study[J]. J Indian Soc Periodontol, 2016, 20(3): 265-272.
27 Nibali L, Darbar U, Rakmanee T, et al. Anemia of inflammation associated with periodontitis: analysis of two clinical studies[J]. J Periodontol, 2019, 90(11): 1252-1259.
28 Lainson PA, Brady PP, Fraleigh CM. Anemia, a systemic cause of periodontal disease[J]. J Periodontol, 1968, 39(1): 35-38.
29 Yamamoto T, Tsuneishi M, Furuta M, et al. Relationship between decrease of erythrocyte count and progression of periodontal disease in a rural Japanese population[J]. J Periodontol, 2011, 82(1): 106-113.
30 Patel MD, Shakir QJ, Shetty A. Interrelationship between chronic periodontitis and anemia: a 6-month follow-up study[J]. J Indian Soc Periodontol, 2014, 18(1): 19-25.
31 Singh PK, Parsek MR, Greenberg EP, et al. A component of innate immunity prevents bacterial biofilm development[J]. Nature, 2002, 417(6888): 552-555.
32 Zandman-Goddard G, Shoenfeld Y. Ferritin in autoimmune diseases[J]. Autoimmun Rev, 2007, 6(7): 457-463.
33 Cairo F, Nieri M, Gori AM, et al. Markers of systemic inflammation in periodontal patients: chronic versus aggressive periodontitis. An explorative cross-sectional study[J]. Eur J Oral Implantol, 2010, 3(2): 147-153.
34 Loos BG. Systemic markers of inflammation in periodontitis[J]. J Periodontol, 2005, 76(11-s): 2106-2115.
35 Guo LN, Yang YZ, Feng YZ. Serum and salivary ferritin and hepcidin levels in patients with chronic periodontitis and type 2 diabetes mellitus[J]. BMC Oral Health, 2018, 18(1): 63.
36 Vilela EM, Bastos JA, Fernandes N, et al. Treatment of chronic periodontitis decreases serum prohepcidin levels in patients with chronic kidney disease[J]. Clinics (Sao Paulo), 2011, 66(4): 657-662.
37 Carvalho RC, Leite SA, Rodrigues VP, et al. Chro-nic periodontitis and serum levels of hepcidin and hemoglobin[J]. Oral Dis, 2016, 22(1): 75-76.
38 Chakraborty S, Tewari S, Sharma RK, et al. Effect of non-surgical periodontal therapy on serum ferritin levels: an interventional study[J]. J Periodontol, 2014, 85(5): 688-696.
39 Huang WX, Li W, Liu J, et al. Ferritin expression in the periodontal tissues of primates[J]. Eur J Histochem, 2019, 63(3): 3046.
40 Huang WX, Zhan YL, Zheng YF, et al. Up-regula-ted ferritin in periodontitis promotes inflammatory cytokine expression in human periodontal ligament cells through transferrin receptor via ERK/P38 MAPK pathways[J]. Clin Sci (Lond), 2019, 133(1): 135-148.
41 Shirmohamadi A, Chitsazi MT, Faramarzi M, et al. Effect of non-surgical periodontal treatment on transferrin serum levels in patients with chronic periodontitis[J]. J Dent Res Dent Clin Dent Prospects, 2016, 10(3): 169-175.
42 Siebert S, Tsoukas A, Robertson J, et al. Cytokines as therapeutic targets in rheumatoid arthritis and o-ther inflammatory diseases[J]. Pharmacol Rev, 2015, 67(2): 280-309.
43 Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type Ⅱ acute-phase protein[J]. Blood, 2003, 101(7): 2461-2463.
44 Nemeth E, Rivera S, Gabayan V, et al. IL-6 media-tes hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin[J]. J Clin Invest, 2004, 113(9): 1271-1276.
45 Cardoso EM, Reis C, Manzanares-Céspedes MC. Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases[J]. Postgrad Med, 2018, 130(1): 98-104.
46 Han Y, Huang WX, Meng HX, et al. Pro-inflammatory cytokine interleukin-6-induced hepcidin, a key mediator of periodontitis-related anemia of inflammation[J]. J Periodont Res, 2021, 56(4): 690-701.
47 Means RT Jr, Dessypris EN, Krantz SB. Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon[J]. J Cell Physiol, 1992, 150(1): 59-64.
48 Correll CK, Binstadt BA. Advances in the pathoge-nesis and treatment of systemic juvenile idiopathic arthritis[J]. Pediatr Res, 2014, 75(1/2): 176-183.
[1] Fu Yu, He Wei, Huang Lan. Ferroptosis and its implication in oral diseases [J]. Int J Stomatol, 2024, 51(1): 36-44.
[2] Luo Xiaojie,Wang Dexu,Chen Xiaotao. Relationship between periodontitis and ferroptosis based on bioinformatics analysis [J]. Int J Stomatol, 2023, 50(6): 661-668.
[3] Huang Yuanhong,Peng Xian,Zhou Xuedong.. Progress in research into the effect of Rhizoma Drynariae on the treatment of bone-related diseases in the oral cavity [J]. Int J Stomatol, 2023, 50(6): 679-685.
[4] Hu Jia,Wang Xiuqing,Lu Guoying,Huang Xiaojing.. Regenerative endodontic procedures for permanent tooth with immature apices in adult patients [J]. Int J Stomatol, 2023, 50(6): 686-695.
[5] Gong Meiling,Cheng Xingqun,Wu Hongkun.. Research progress on the correlation between Parkinson’s disease and periodontitis [J]. Int J Stomatol, 2023, 50(5): 587-593.
[6] Xu Zhibo,Meng Xiuping.. Research progress on mechanism of Enterococcus faecalis escaping host immune defense [J]. Int J Stomatol, 2023, 50(5): 613-617.
[7] Liang Zhiying,Zhao Yuanxi,Zhu Jiani,Su Qin.. Retrospective analysis of clinical data of 288 cases of endodontic microsurgery on anterior teeth [J]. Int J Stomatol, 2023, 50(2): 166-171.
[8] Liu Tiqian,Liang Xing,Liu Weiqing,Li Xiaohong,Zhu Rui.. Research progress on the role and mechanism of occlusal trauma in the development of periodontitis [J]. Int J Stomatol, 2023, 50(1): 19-24.
[9] Li Qiong,Yu Weixian. Research progress on resveratrol for the treatment of periodontitis and its bioavailability [J]. Int J Stomatol, 2023, 50(1): 25-31.
[10] Huang Weikun,Xu Qiuyan,Zhou Ting.. Role of baicalin and mechanisms through which baicalin attenuates oxidative stress injury induced by lipopolysaccharide on macrophages [J]. Int J Stomatol, 2022, 49(5): 521-528.
[11] Zhou Jianpeng,Xie Xudong,Zhao Lei,Wang Jun.. Research progress on the roles and mechanisms of T-helper 17 cells and interleukin-17 in periodontitis [J]. Int J Stomatol, 2022, 49(5): 586-592.
[12] Chen Huiyu,Bai Mingru,Ye Ling.. Progress in understanding the correlations between semaphorin 3A and common oral diseases [J]. Int J Stomatol, 2022, 49(5): 593-599.
[13] Zhou Jiajia,Zhao Lei,Xu Xin. Research progress on the genetic polymorphism of periodontitis [J]. Int J Stomatol, 2022, 49(4): 432-440.
[14] Zhu Jiani,Su Qin. Research status of the use of root canal and periapical microflora in refractory periapical periodontitis [J]. Int J Stomatol, 2022, 49(3): 283-289.
[15] Ma Yu,Zuo Yu,Zhang Xin. Photodynamic therapy as an adjunct to periodontitis: a meta-analysis [J]. Int J Stomatol, 2022, 49(3): 305-316.
Full text



[1] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[2] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[3] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[4] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[5] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[6] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[7] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[8] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[9] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[10] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .