Skip to main content
Top
Published in: Inflammation Research 4/2018

01-04-2018 | Original Research Paper

Methylation of cytokines gene promoters in IL-1β-treated human intestinal epithelial cells

Authors: Fabio Caradonna, Ilenia Cruciata, Ilaria Schifano, Chiara La Rosa, Flores Naselli, Roberto Chiarelli, Anna Perrone, Carla Gentile

Published in: Inflammation Research | Issue 4/2018

Login to get access

Abstract

Objective and design

Epigenetic regulation is important in the activation of inflammatory cells. In the present study, we evaluated if DNA-methylation variations are involved in Interleukin-1β (IL-1β)-induced intestinal epithelial cells activation.

Materials and methods

Differentiated Caco-2 cells were exposed to IL-1β or to 5-azadeoxycytidine (5-azadC) for 24 or 48 h. Genome-wide methylation status was evaluated, while DNA methylation status at the promoter region of the gene encoding interleukin-6, 8 and 10 (IL-6, 8 and 10) was estimated. The levels of the corresponding gene products as well as DNA methyltransferases (DNMTs) quantity were assessed.

Results

IL-1β decreased genomic methylation of human intestinal epithelial cells and induced demethylation at cg-specific sites at the promoter of pro-inflammatory genes IL6 and IL8; conversely it did not change the methylation of the IL10 promoter. IL-1β also increased the release of IL-6 and IL-8 but did not change the IL-10 expression. Finally, cell exposure to IL-1β decreased the DNMT3b expression, increased DNMT3a and was not able to change DNMT1 expression.

Conclusions

Our results suggest a potential role of IL-1β as modulator of DNA methylation in activated differentiated Caco-2 cell line.
Appendix
Available only for authorised users
Literature
1.
go back to reference Martin GR, Wallace JL. Gastrointestinal inflammation: a central component of mucosal defense and repair. Exp Biol Med. 2006;231:130–7.CrossRef Martin GR, Wallace JL. Gastrointestinal inflammation: a central component of mucosal defense and repair. Exp Biol Med. 2006;231:130–7.CrossRef
2.
go back to reference Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka-Wroblewska E, Kagnoff MF. A distinct array of pro-inflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest. 1995;95(1):55–65.CrossRefPubMedPubMedCentral Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka-Wroblewska E, Kagnoff MF. A distinct array of pro-inflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest. 1995;95(1):55–65.CrossRefPubMedPubMedCentral
3.
go back to reference Van De Walle J, Hendrickx A, Romier B, Larondelle Y, Schneider YJ. Inflammatory parameters in Caco-2 cells: Effect of stimuli nature, concentration, combination and cell differentiation. Toxicol In Vitro. 2010;24(5):1441–9.CrossRef Van De Walle J, Hendrickx A, Romier B, Larondelle Y, Schneider YJ. Inflammatory parameters in Caco-2 cells: Effect of stimuli nature, concentration, combination and cell differentiation. Toxicol In Vitro. 2010;24(5):1441–9.CrossRef
4.
go back to reference Böcker U, Yezerskyy O, Feick P, Manigold T, Panja A, Kalina U, Herweck F, Rossol S, Singer MV. Responsiveness of intestinal epithelial cell lines to lipopolysaccharide is correlated with Toll-like receptor 4 but not Toll-like receptor 2 or CD14 expression. Int J Colorectal Dis. 2003;18(1):25–32.CrossRefPubMed Böcker U, Yezerskyy O, Feick P, Manigold T, Panja A, Kalina U, Herweck F, Rossol S, Singer MV. Responsiveness of intestinal epithelial cell lines to lipopolysaccharide is correlated with Toll-like receptor 4 but not Toll-like receptor 2 or CD14 expression. Int J Colorectal Dis. 2003;18(1):25–32.CrossRefPubMed
5.
go back to reference Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointestn Liver Physiol. 2004;287(1):G7–G17.CrossRef Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointestn Liver Physiol. 2004;287(1):G7–G17.CrossRef
6.
go back to reference Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94(1):174–81.CrossRefPubMedPubMedCentral Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94(1):174–81.CrossRefPubMedPubMedCentral
7.
go back to reference Latorre E, Mendoza C, Matheus N, Castro M, Grasa L, Mesonero JE, Alcalde AI. IL-10 modulates serotonin transporter activity and molecular expression in intestinal epithelial cells. Cytokine. 2013;61(3):778–84.CrossRefPubMed Latorre E, Mendoza C, Matheus N, Castro M, Grasa L, Mesonero JE, Alcalde AI. IL-10 modulates serotonin transporter activity and molecular expression in intestinal epithelial cells. Cytokine. 2013;61(3):778–84.CrossRefPubMed
8.
go back to reference Fonseca-Camarillo G, Yamamoto-Furusho JK. Gene expression of solute carrier family 9 (sodium/hydrogen exchanger) 3, (SLC9A3) is downregulated in patients with ulcerative colitis. Inflamm Bowel Dis. 2012;18(6):1197–8.CrossRefPubMed Fonseca-Camarillo G, Yamamoto-Furusho JK. Gene expression of solute carrier family 9 (sodium/hydrogen exchanger) 3, (SLC9A3) is downregulated in patients with ulcerative colitis. Inflamm Bowel Dis. 2012;18(6):1197–8.CrossRefPubMed
9.
go back to reference Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, Ichinose M, Tatematsu M, Ushijima T. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70(4):1430–40.CrossRefPubMed Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, Ichinose M, Tatematsu M, Ushijima T. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70(4):1430–40.CrossRefPubMed
10.
go back to reference Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov. 2009;3(1):73–80.CrossRefPubMed Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov. 2009;3(1):73–80.CrossRefPubMed
11.
go back to reference Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–73.CrossRefPubMedPubMedCentral Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–73.CrossRefPubMedPubMedCentral
12.
go back to reference Wells AD. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol. 2009;182(12):7331–41.CrossRefPubMed Wells AD. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol. 2009;182(12):7331–41.CrossRefPubMed
13.
14.
go back to reference Villagra A, Sotomayor EM, Seto E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene. 2010;29(2):157–73.CrossRefPubMed Villagra A, Sotomayor EM, Seto E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene. 2010;29(2):157–73.CrossRefPubMed
15.
go back to reference Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905–17.CrossRefPubMed Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905–17.CrossRefPubMed
16.
go back to reference Shuto T, Furuta T, Oba M, Xu H, Li JD, Cheung J, Gruenert DC, Uehara A, Suico MA, Okiyoneda T, Kai H. Promoter hypomethylation of Toll-like receptor-2 gene is associated with increased pro-inflammatory response toward bacterial peptidoglycan in cystic fibrosis bronchial epithelial cells. FASEB J. 2006;20(6):782–4.CrossRefPubMed Shuto T, Furuta T, Oba M, Xu H, Li JD, Cheung J, Gruenert DC, Uehara A, Suico MA, Okiyoneda T, Kai H. Promoter hypomethylation of Toll-like receptor-2 gene is associated with increased pro-inflammatory response toward bacterial peptidoglycan in cystic fibrosis bronchial epithelial cells. FASEB J. 2006;20(6):782–4.CrossRefPubMed
17.
go back to reference Takahashi K, Sugi Y, Hosono A, Kaminogawa S. Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol. 2009;183(10):6522–9.CrossRefPubMed Takahashi K, Sugi Y, Hosono A, Kaminogawa S. Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol. 2009;183(10):6522–9.CrossRefPubMed
18.
go back to reference Katayama Y, Takahashi M, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun. 2009;388(3):496–500.CrossRefPubMed Katayama Y, Takahashi M, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun. 2009;388(3):496–500.CrossRefPubMed
19.
go back to reference Ding SZ, Goldberg JB, Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis. Future Oncol. 2010;6(5):851–62.CrossRefPubMedPubMedCentral Ding SZ, Goldberg JB, Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis. Future Oncol. 2010;6(5):851–62.CrossRefPubMedPubMedCentral
20.
go back to reference Gentile C, Perrone A, Attanzio A, Tesoriere L, Livrea MA. Sicilian pistachio (Pistacia vera L.) nut inhibits expression and release of inflammatory mediators and reverts the increase of paracellular permeability in IL-1β-exposed human intestinal epithelial cells. Eur J Nutr. 2015;54(5):811–21.CrossRefPubMed Gentile C, Perrone A, Attanzio A, Tesoriere L, Livrea MA. Sicilian pistachio (Pistacia vera L.) nut inhibits expression and release of inflammatory mediators and reverts the increase of paracellular permeability in IL-1β-exposed human intestinal epithelial cells. Eur J Nutr. 2015;54(5):811–21.CrossRefPubMed
21.
go back to reference Catanzaro I, Caradonna F, Barbata G, Saverini M, Mauro M, Sciandrello G. Genomic instability induced by α-pinene in Chinese hamster cell line. Mutagenesis. 2012;27(4):463–9.CrossRefPubMed Catanzaro I, Caradonna F, Barbata G, Saverini M, Mauro M, Sciandrello G. Genomic instability induced by α-pinene in Chinese hamster cell line. Mutagenesis. 2012;27(4):463–9.CrossRefPubMed
22.
go back to reference Naselli F, Belshaw NJ, Gentile C, Tutone M, Tesoriere L, Livrea MA, Caradonna F. Phytochemical indicaxanthin inhibits colon cancer cell growth and affects the DNA methylation status by influencing epigenetically modifying enzyme expression and activity. J Nutrigenet Nutrigenom. 2015;8:114–27.CrossRef Naselli F, Belshaw NJ, Gentile C, Tutone M, Tesoriere L, Livrea MA, Caradonna F. Phytochemical indicaxanthin inhibits colon cancer cell growth and affects the DNA methylation status by influencing epigenetically modifying enzyme expression and activity. J Nutrigenet Nutrigenom. 2015;8:114–27.CrossRef
23.
go back to reference Mauro M, Caradonna F, Klein CB. Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells. Environ Mol Mutagen. 2016;57(2):137–50.CrossRefPubMed Mauro M, Caradonna F, Klein CB. Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells. Environ Mol Mutagen. 2016;57(2):137–50.CrossRefPubMed
24.
go back to reference Bellavia D, Dimarco E, Caradonna F. Characterization of three different clusters of 18S-26S ribosomal DNA genes in the sea urchin P. lividus: Genetic and epigenetic regulation synchronous to 5S rDNA. Gene 2016;580(2):118–24. Bellavia D, Dimarco E, Caradonna F. Characterization of three different clusters of 18S-26S ribosomal DNA genes in the sea urchin P. lividus: Genetic and epigenetic regulation synchronous to 5S rDNA. Gene 2016;580(2):118–24.
25.
go back to reference Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008;58(9): 2686–93.CrossRefPubMed Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008;58(9): 2686–93.CrossRefPubMed
26.
go back to reference Takahashi A, de Andrés MC, Hashimoto K, Itoi E, Oreffo RO. Epigenetic regulation of interleukin-8, an inflammatory chemokine, in osteoarthritis. Osteoarthr Cartil. 2015;23:1946–54.CrossRefPubMedPubMedCentral Takahashi A, de Andrés MC, Hashimoto K, Itoi E, Oreffo RO. Epigenetic regulation of interleukin-8, an inflammatory chemokine, in osteoarthritis. Osteoarthr Cartil. 2015;23:1946–54.CrossRefPubMedPubMedCentral
27.
go back to reference Larsson L, Thorbert-Mros S, Rymo L, Berglundh T. Influence of epigenetic modifications of the interleukin-10 promoter on IL10 gene expression. Eur J Oral Sci. 2012;120:14–20.CrossRefPubMed Larsson L, Thorbert-Mros S, Rymo L, Berglundh T. Influence of epigenetic modifications of the interleukin-10 promoter on IL10 gene expression. Eur J Oral Sci. 2012;120:14–20.CrossRefPubMed
28.
go back to reference Bellavia D, Dimarco E, Naselli F, Caradonna F. DNA-methylation dependent regulation of embryo-specific 5S ribosomal DNA cluster transcription in adult tissues of sea urchin Paracentrotus lividus. Genomics. 2013;102:397–402.CrossRefPubMed Bellavia D, Dimarco E, Naselli F, Caradonna F. DNA-methylation dependent regulation of embryo-specific 5S ribosomal DNA cluster transcription in adult tissues of sea urchin Paracentrotus lividus. Genomics. 2013;102:397–402.CrossRefPubMed
29.
go back to reference Librizzi M, Chiarelli R, Bosco L, Sansook S, Gascon JM, Spencer J, Caradonna F, Luparello C. The histone deacetylase inhibitor JAHA down-regulates pERK and global DNA methylation in MDA-MB231 breast cancer cells. Materials. 2015;8(10):7041–7.CrossRefPubMedPubMedCentral Librizzi M, Chiarelli R, Bosco L, Sansook S, Gascon JM, Spencer J, Caradonna F, Luparello C. The histone deacetylase inhibitor JAHA down-regulates pERK and global DNA methylation in MDA-MB231 breast cancer cells. Materials. 2015;8(10):7041–7.CrossRefPubMedPubMedCentral
30.
go back to reference Chiarelli R, Agnello M, Roccheri MC. Sea urchin embryo as a model system for studying autophagy induced by cadmium stress. Autophagy. 2011;7:1028–34.CrossRefPubMed Chiarelli R, Agnello M, Roccheri MC. Sea urchin embryo as a model system for studying autophagy induced by cadmium stress. Autophagy. 2011;7:1028–34.CrossRefPubMed
31.
go back to reference Sciandrello G, Mauro M, Caradonna F, Catanzaro I, Saverini M, Barbata G. Acrylamide catalytically inhibits topoisomerase II in V79 cells. Toxicol In Vitro. 2010;24(3):830–4.CrossRefPubMed Sciandrello G, Mauro M, Caradonna F, Catanzaro I, Saverini M, Barbata G. Acrylamide catalytically inhibits topoisomerase II in V79 cells. Toxicol In Vitro. 2010;24(3):830–4.CrossRefPubMed
32.
go back to reference Sambuy Y, De Angelis I, Ranaldi G, Scarino ML, Stammati A, Zucco F. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005;21(1):1–26.CrossRefPubMed Sambuy Y, De Angelis I, Ranaldi G, Scarino ML, Stammati A, Zucco F. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005;21(1):1–26.CrossRefPubMed
33.
go back to reference Behrens I, Kissel T. Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2 cell monolayers? Eur J Pharm Sci. 2003;19(5):433–42.CrossRefPubMed Behrens I, Kissel T. Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2 cell monolayers? Eur J Pharm Sci. 2003;19(5):433–42.CrossRefPubMed
34.
go back to reference Shanmugam MK, Sethi G. Role of epigenetics in inflammation-associated diseases. Subcell Biochem. 2013;61:627–57.CrossRefPubMed Shanmugam MK, Sethi G. Role of epigenetics in inflammation-associated diseases. Subcell Biochem. 2013;61:627–57.CrossRefPubMed
35.
go back to reference Cole MB, Quach H, Quach D, Alice B, Taylor KE, Barcellos LF, Criswell LA. Epigenetic signatures of salivary gland inflammation in Sjögren's syndrome. Arthritis Rheumatol. 2016;68(12):2936–44.CrossRefPubMedPubMedCentral Cole MB, Quach H, Quach D, Alice B, Taylor KE, Barcellos LF, Criswell LA. Epigenetic signatures of salivary gland inflammation in Sjögren's syndrome. Arthritis Rheumatol. 2016;68(12):2936–44.CrossRefPubMedPubMedCentral
36.
go back to reference Sarabi MM, Naghibalhossaini F. Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells. Cell Biochem Funct. 2015;33:427–33.CrossRefPubMed Sarabi MM, Naghibalhossaini F. Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells. Cell Biochem Funct. 2015;33:427–33.CrossRefPubMed
37.
go back to reference Choi SH, Heo K, Byun HM, An W, Lu W, Yang AS. Identification of preferential target sites for human DNA methyltransferases. Nucleic Acids Res. 2011;39:104–18.CrossRefPubMed Choi SH, Heo K, Byun HM, An W, Lu W, Yang AS. Identification of preferential target sites for human DNA methyltransferases. Nucleic Acids Res. 2011;39:104–18.CrossRefPubMed
38.
go back to reference Wang B, Cui Z, Zhong Z, Sun Y, Yang GY, Sun Q, Bian L. The role and regulatory mechanism of IL-1β on the methylation of the NF2 gene in benign meningiomas and leptomeninges. Mol Carcinog. 2016;55(12):2268–77.CrossRefPubMed Wang B, Cui Z, Zhong Z, Sun Y, Yang GY, Sun Q, Bian L. The role and regulatory mechanism of IL-1β on the methylation of the NF2 gene in benign meningiomas and leptomeninges. Mol Carcinog. 2016;55(12):2268–77.CrossRefPubMed
39.
go back to reference Nakano K, Boyle DL, Firestein GS. Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J Immunol. 2013;190(3):1297–303.CrossRefPubMed Nakano K, Boyle DL, Firestein GS. Regulation of DNA methylation in rheumatoid arthritis synoviocytes. J Immunol. 2013;190(3):1297–303.CrossRefPubMed
40.
go back to reference Naselli F, Tesoriere L, Caradonna F, Bellavia D, Attanzio A, Gentile C, Livrea MA. Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16(INK4a) gene in human colorectal carcinoma (Caco-2) cells. Biochem Biophys Res Commun. 2014;450(1):652–8.CrossRefPubMed Naselli F, Tesoriere L, Caradonna F, Bellavia D, Attanzio A, Gentile C, Livrea MA. Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16(INK4a) gene in human colorectal carcinoma (Caco-2) cells. Biochem Biophys Res Commun. 2014;450(1):652–8.CrossRefPubMed
Metadata
Title
Methylation of cytokines gene promoters in IL-1β-treated human intestinal epithelial cells
Authors
Fabio Caradonna
Ilenia Cruciata
Ilaria Schifano
Chiara La Rosa
Flores Naselli
Roberto Chiarelli
Anna Perrone
Carla Gentile
Publication date
01-04-2018
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 4/2018
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-017-1124-5

Other articles of this Issue 4/2018

Inflammation Research 4/2018 Go to the issue