nach oben

Erschienen in:

07.01.2021 | Original Article

Localization of interleukin-6 signaling complex in epithelialized apical lesions of endodontic origin

verfasst von: C. Schweitzer, M. Garrido, R. Paredes, C. Stoore, M. Reyes, R. Bologna-Molina, A. Fernández, Marcela Hernández Rios

Erschienen in: Clinical Oral Investigations | Ausgabe 6/2021

Einloggen, um Zugang zu erhalten

Abstract

Objectives

We aimed to determine the immunolocalization patterns of the interleukin (IL)-6 signaling complex in epithelialized and non-epithelialized apical lesions of endodontic origin (ALEOs).

Materials and methods

Epithelialized (n = 8) and non-epithelialized (n = 7) ALEOs were obtained from teeth with indication of extraction in patients with clinical diagnosis of apical periodontitis. All tissues were subjected to routine processing for histopathologic examination and primary antibodies for IL-6, IL-6 receptor (R), and glycoprotein (gp)-130 were used for immunohistochemistry and double immunofluorescence co-localization.

Results

IL-6, IL-6R, and gp-130 were immunolocalized in endothelial cells and mononuclear leukocytes in a diffuse pattern within the connective tissue of epithelialized and non-epithelialized ALEOs. In the epithelialized lesions, two different patterns were identified: IL-6 signaling complex was localized within the proliferating epithelium in a diffuse intracellular pattern and in a cell membrane localization pattern within the mature epithelial lining, showing a decreased intensity towards the surface layers.

Conclusions

IL-6, IL-6R, and gp-130 localized to mononuclear inflammatory cells, vascular endothelial cells, and immature proliferating epithelia in a diffuse pattern and in mature lining epithelia in a localized cell membrane pattern, supporting a role for epithelial proliferation during cyst formation. Additional cell membrane co-localization of IL-6 receptor complex suggests classic signaling involvement in addition to trans-signaling.

Garrido M, Dezerega A, Bordagaray MJ, Reyes M, Vernal R, Melgar-Rodriguez S, Ciuchi P, Paredes R, Garcia-Sesnich J, Ahumada-Montalva P, Hernandez M (2015) C-reactive protein expression is up-regulated in apical lesions of endodontic origin in association with interleukin-6. J Endod 41(4):464–469. https://doi.org/10.1016/j.joen.2014.12.021CrossRefPubMed

Garrido M, Cardenas AM, Astorga J, Quinlan F, Valdes M, Chaparro A, Carvajal P, Pussinen P, Huaman-Chipana P, Jalil JE, Hernandez M (2019) Elevated systemic inflammatory burden and cardiovascular risk in young adults with endodontic apical lesions. J Endod 45(2):111–115. https://doi.org/10.1016/j.joen.2018.11.014CrossRefPubMed

Bernardi L, Visioli F, Nör C, Rados PV (2015) Radicular cyst: an update of the biological factors related to lining epithelium. J Endod 41(12):1951–1961. https://doi.org/10.1016/j.joen.2015.08.036CrossRefPubMed

Çalışkan MK, Kaval ME, Tekin U, Ünal T (2016) Radiographic and histological evaluation of persistent periapical lesions associated with endodontic failures after apical microsurgery. Int Endod J 49(11):1011–1019. https://doi.org/10.1111/iej.12554CrossRefPubMed

Vidal F, Fontes TV, Marques TV, Gonçalves LS (2016) Association between apical periodontitis lesions and plasmatic levels of C-reactive protein, interleukin 6 and fibrinogen in hypertensive patients. Int Endod J 49(12):1107–1115. https://doi.org/10.1111/iej.12567CrossRefPubMed

Prso IB, Kocjan W, Simic H, Brumini G, Pezelj-Ribaric S, Borcic J, Ferreri S, Karlovic IM (2007) Tumor necrosis factor-alpha and interleukin 6 in human periapical lesions. Mediat Inflamm 2007:38210–38214. https://doi.org/10.1155/2007/38210CrossRef

Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS (2014) IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One 9(12):e114195. https://doi.org/10.1371/journal.pone.0114195CrossRefPubMedPubMedCentral

Rose-John S, Winthrop K, Calabrese L (2017) The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol 13(7):399–409. https://doi.org/10.1038/nrrheum.2017.83CrossRefPubMed

Gabay C, Silacci P, Genin B, Mentha G, Le Coultre C, Guerne PA (1995) Soluble interleukin-6 receptor strongly increases the production of acute-phase protein by hepatoma cells but exerts minimal changes on human primary hepatocytes. Eur J Immunol 25(8):2378–2383. https://doi.org/10.1002/eji.1830250838CrossRefPubMed

10.

Garbers C, Thaiss W, Jones GW, Waetzig GH, Lorenzen I, Guilhot F, Lissilaa R, Ferlin WG, Grötzinger J, Jones SA, Rose-John S, Scheller J (2011) Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. J Biol Chem 286(50):42959–42970. https://doi.org/10.1074/jbc.M111.295758CrossRefPubMedPubMedCentral

11.

Flynn CM, Garbers Y, Lokau J, Wesch D, Schulte DM, Laudes M, Lieb W, Aparicio-Siegmund S, Garbers C (2019) Activation of Toll-like receptor 2 (TLR2) induces interleukin-6 trans-signaling. Sci Rep 9(1):7306. https://doi.org/10.1038/s41598-019-43617-5CrossRefPubMedPubMedCentral

12.

Hernández-Caldera A, Vernal R, Paredes R, Veloso-Matta P, Astorga J, Hernández M (2017) Human periodontal ligament fibroblasts synthesize C-reactive protein and Th-related cytokines in response to interleukin (IL)-6 trans-signalling. Int Endod J 51:632–640. https://doi.org/10.1111/iej.12872CrossRefPubMed

13.

Fernández A, Veloso P, Astorga J, Rodríguez C, Torres VA, Valdés M, Garrido M, Gebicke-Haerter PJ, Hernández M (2020) Epigenetic regulation of TLR2-mediated periapical inflammation. Int Endod J 53:1229–1237. https://doi.org/10.1111/iej.13329CrossRefPubMed

14.

Veloso P, Fernandez A, Terraza-Aguirre C, Alvarez C, Vernal R, Escobar A, Hernandez M (2020) Macrophages skew towards M1 profile through reduced CD163 expression in symptomatic apical periodontitis. Clin Oral Investig 24:4571–4581. https://doi.org/10.1007/s00784-020-03324-2CrossRefPubMed

15.

Euler GJ, Miller GA, Hutter JW, D’Alesandro MM (1998) Interleukin-6 in neutrophils from peripheral blood and inflammatory periradicular tissues. J Endod 24(7):480–484. https://doi.org/10.1016/S0099-2399(98)80051-4CrossRefPubMed

16.

Okada N, Kobayashi M, Mugikura K, Okamatsu Y, Hanazawa S, Kitano S, Hasegawa K (1997) Interleukin-6 production in human fibroblasts derived from periodontal tissues is differentially regulated by cytokines and a glucocorticoid. J Periodontal Res 32(7):559–569CrossRef

17.

Neiva KG, Warner KA, Campos MS, Zhang Z, Moren J, Danciu TE, Nör JE (2014) Endothelial cell-derived interleukin-6 regulates tumor growth. BMC Cancer 14:99. https://doi.org/10.1186/1471-2407-14-99CrossRefPubMedPubMedCentral

18.

Triantafilou M, Gamper FG, Lepper PM, Mouratis MA, Schumann C, Harokopakis E, Schifferle RE, Hajishengallis G, Triantafilou K (2007) Lipopolysaccharides from atherosclerosis-associated bacteria antagonize TLR4, induce formation of TLR2/1/CD36 complexes in lipid rafts and trigger TLR2-induced inflammatory responses in human vascular endothelial cells. Cell Microbiol 9(8):2030–2039. https://doi.org/10.1111/j.1462-5822.2007.00935.xCrossRefPubMed

19.

Jablonska E, Marcinczyk M (2003) Role of interleukin-15 and interleukin-18 in the secretion of sIL-6R and sgp130 by human neutrophils. Mediat Inflamm 12(3):179–183. https://doi.org/10.1080/0962935031000134905CrossRef

20.

Wang Y, Lewis DF, Gu Y, Zhao S, Groome LJ (2011) Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia. Hypertension 57(2):336–342. https://doi.org/10.1161/HYPERTENSIONAHA.110.163360CrossRefPubMed

21.

Aden K, Breuer A, Rehman A, Geese H, Tran F, Sommer J, Waetzig GH, Reinheimer TM, Schreiber S, Rose-John S, Scheller J, Rosenstiel P (2016) Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair. Oncogenesis 5(11):e270. https://doi.org/10.1038/oncsis.2016.71CrossRefPubMedPubMedCentral

22.

Polgár A, Brózik M, Tóth S, Holub M, Hegyi K, Kádár A, Hodinka L, Falus A (2000) Soluble interleukin-6 receptor in plasma and in lymphocyte culture supernatants of healthy individuals and patients with systemic lupus erythematosus and rheumatoid arthritis. Med Sci Monit 6(1):13–18PubMed

23.

Sawada S, Chosa N, Ishisaki A, Naruishi K (2013) Enhancement of gingival inflammation induced by synergism of IL-1β and IL-6. Biomed Res 34(1):31–40CrossRef

24.

Bracks IV, Armada L, Gonçalves LS, Pires FR (2014) Distribution of mast cells and macrophages and expression of interleukin-6 in periapical cysts. J Endod 40(1):63–68. https://doi.org/10.1016/j.joen.2013.09.037CrossRefPubMed

25.

Miyagawa T, Fujita T, Ouhara K, Matsuda S, Kajiya M, Hayashida K, Imai H, Yoshimoto T, Iwata T, Shiba H, Abiko Y, Kurihara H (2013) Irsogladine maleate regulates the inflammatory related genes in human gingival epithelial cells stimulated by Aggregatibacter actinomycetemcomitans. Int Immunopharmacol 15(2):340–347. https://doi.org/10.1016/j.intimp.2012.12.011CrossRefPubMed

26.

Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S (1999) Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res 90(8):858–866CrossRef

27.

Rodríguez-Berriguete G, Prieto A, Fraile B, Bouraoui Y, de Bethencourt FR, Martínez-Onsurbe P, Olmedilla G, Paniagua R, Royuela M (2010) Relationship between IL-6/ERK and NF-κB: a study in normal and pathological human prostate gland. Eur Cytokine Netw 21(4):241–250. https://doi.org/10.1684/ecn.2010.0211CrossRefPubMed

28.

Kim JH, Han IH, Kim YS, Noh CS, Ryu JS (2018) Proliferation of prostate epithelia induced by IL-6 from stroma reacted with Trichomonas vaginalis. Parasite Immunol 40(6):e12531. https://doi.org/10.1111/pim.12531CrossRefPubMed

29.

Zhang G, Tsang CM, Deng W, Yip YL, Lui VW, Wong SC, Cheung AL, Hau PM, Zeng M, Lung ML, Chen H, Lo KW, Takada K, Tsao SW (2013) Enhanced IL-6/IL-6R signaling promotes growth and malignant properties in EBV-infected premalignant and cancerous nasopharyngeal epithelial cells. PLoS One 8(5):e62284. https://doi.org/10.1371/journal.pone.0062284CrossRefPubMedPubMedCentral

30.

Wouters M, Dijkgraaf EM, Kuijjer ML, Jordanova ES, Hollema H, Welters M, van der Hoeven J, Daemen T, Kroep JR, Nijman HW, van der Burg SH (2014) Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer. Oncoimmunology 3(12):e962397. https://doi.org/10.4161/21624011.2014.962397CrossRefPubMed

31.

Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A (2011) Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing. Invest Ophthalmol Vis Sci 52(12):8549–8557. https://doi.org/10.1167/iovs.11-7956CrossRefPubMed

32.

Feng W, Liu H, Luo T, Liu D, Du J, Sun J, Wang W, Han X, Yang K, Guo J, Amizuka N, Li M (2017) Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways. Sci Rep 7:41411. https://doi.org/10.1038/srep41411CrossRefPubMedPubMedCentral

33.

Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8(9):1237–1247. https://doi.org/10.7150/ijbs.4989CrossRefPubMedPubMedCentral

34.

Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813(5):878–888. https://doi.org/10.1016/j.bbamcr.2011.01.034CrossRefPubMed

Titel: Localization of interleukin-6 signaling complex in epithelialized apical lesions of endodontic origin
verfasst von: C. Schweitzer
M. Garrido
R. Paredes
C. Stoore
M. Reyes
R. Bologna-Molina
A. Fernández
Marcela Hernández Rios
Publikationsdatum: 07.01.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Clinical Oral Investigations / Ausgabe 6/2021
Print ISSN: 1432-6981
Elektronische ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-020-03738-y

Bestellen Sie unseren kostenlosen Newsletter Update Zahnmedizin und bleiben Sie gut informiert – ganz bequem per eMail.

Newsletter bestellen

Springer Medizin

Localization of interleukin-6 signaling complex in epithelialized apical lesions of endodontic origin