The Relationship between Type 1 Diabetes Mellitus, TNF-α, and IL-10 Gene Expression

Jesselina Francisco Dos Santos Haber, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos de Argollo Haber, Roger William de Labio, Lucas Fornari Laurindo, Eduardo Federighi Baisi Chagas, Spencer Luiz Marques Payão, Jesselina Francisco Dos Santos Haber, Sandra Maria Barbalho, Jose Augusto Sgarbi, Rafael Santos de Argollo Haber, Roger William de Labio, Lucas Fornari Laurindo, Eduardo Federighi Baisi Chagas, Spencer Luiz Marques Payão

Abstract

Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, 30 patients had T1DM and HbA1c ≥ 8%; 32 patients had T1DM and presented HbA1c < 8%; and 30 were controls. The expression of peripheral blood mononuclear cells was performed using the reverse transcriptase-polymerase chain reaction in real time. The cytokines gene expression was higher in patients with T1DM. The IL-10 gene expression increased substantially in patients with ketoacidosis, and there was a positive correlation with HbA1c. A negative correlation was found for IL-10 expression and the age of patients with diabetes, and the time of diagnosis of the disease. There was a positive correlation between TNF-α expression with age. The expression of IL-10 and TNF-α genes showed a significant increase in DM1 patients. Once current T1DM treatment is based on exogenous insulin, there is a need for other therapies, and inflammatory biomarkers could bring new possibilities to the therapeutic approach of the patients.

Keywords: HbA1c; gene expression; interleukin 10; ketoacidosis; tumor necrosis factor-α; type 1 diabetes mellitus.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Comparison of the median and interquartile range (box) of IL-10 RQ between groups. Different superscript letters indicate a significant difference between the means by the post hoc Holm–Sidak test for p-value < 0.050. Different superscript letters indicate a significant difference between the means by the post hoc Holm–Sidak test for p-value < 0.050.
Figure 2
Figure 2
Comparison of the mean and 95% confidence interval (error bar) of TNF RQ between groups. Different superscript letters indicate a significant difference between the means by the post hoc Holm–Sidak test for p-value < 0.050.

References

    1. Negrato C.A., Lauris J.R.P., Saggioro I.B., Corradini M.C.M., Borges P.R., Cres M.C., Junior A.L., Guedes M.F.S., Gomes M.B. Increasing incidence of type 1 diabetes between 1986 and 2015 in Bauru, Brazil. Diabetes Res. Clin. Pr. 2017;127:198–204. doi: 10.1016/j.diabres.2017.03.014.
    1. American Diabetes Association Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42:S13–S28. doi: 10.2337/dc19-S002.
    1. Tenenbaum Weiss Y., Friger M., Haim A., Hershkovitz E. Patterns in Body Mass Index Changes in Children after Type 1 Diabetes Mellitus Diagnosis. Isr. Med. Assoc. J. IMAJ. 2023;25:137–142.
    1. Wang Z., Xie Z., Lu Q., Chang C., Zhou Z. Beyond Genetics: What Causes Type 1 Diabetes. Clin. Rev. Allergy Immunol. 2017;52:273–286. doi: 10.1007/s12016-016-8592-1.
    1. DCCT Research Group Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: Observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). The DCCT Research Group. J. Clin. Endocrinol. Metab. 1987;65:30–36. doi: 10.1210/jcem-65-1-30.
    1. Katsarou A., Gudbjornsdottir S., Rawshani A., Dabelea D., Bonifacio E., Anderson B.J., Jacobsen L.M., Schatz D.A., Lernmark A. Type 1 diabetes mellitus. Nat. Rev. Dis. Primers. 2017;3:17016. doi: 10.1038/nrdp.2017.16.
    1. Peakman M. Immunological pathways to β-cell damage in Type 1 diabetes. Diabet. Med. 2013;30:147–154. doi: 10.1111/dme.12085.
    1. Buckner T., Johnson R.K., Vanderlinden L.A., Carry P.M., Romero A., Onengut-Gumuscu S., Chen W.M., Fiehn O., Frohnert B.I., Crume T., et al. An Oxylipin-Related Nutrient Pattern and Risk of Type 1 Diabetes in the Diabetes Autoimmunity Study in the Young (DAISY) Nutrients. 2023;15:945. doi: 10.3390/nu15040945.
    1. Ouyang W., O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: From Basic Science to Clinical Translation. Immunity. 2019;50:871–891. doi: 10.1016/j.immuni.2019.03.020.
    1. Pierson W., Liston A. A new role for interleukin-10 in immune regulation. Immunol. Cell Biol. 2010;88:769–770. doi: 10.1038/icb.2010.105.
    1. Trifunovic J., Miller L., Debeljak Z., Horvat V. Pathologic patterns of interleukin 10 expression--a review. Biochem. Med. 2015;25:36–48. doi: 10.11613/BM.2015.004.
    1. Rutz S., Ouyang W. Regulation of Interleukin-10 Expression. Adv. Exp. Med. Biol. 2016;941:89–116. doi: 10.1007/978-94-024-0921-5_5.
    1. Obasanmi G., Lois N., Armstrong D., Hombrebueno J.M.R., Lynch A., Chen M., Xu H. Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ-A Pilot Study. Cells. 2023;12:467. doi: 10.3390/cells12030467.
    1. Russell M.A., Morgan N.G. The impact of anti-inflammatory cytokines on the pancreatic β-cell. Islets. 2014;6:e950547. doi: 10.4161/19382014.2014.950547.
    1. Nouar M., Miliani M., Belhassena I., Fatmi A., Aribi M. Sodium selenite modulates global activation of proinflammatory M1-like macrophages, necroinflammation and M1-like/M2-like dichotomy at the onset of human type 1 diabetes. Endocr. Metab. Immune Disord. Drug Targets. 2023 doi: 10.2174/1871530323666230201135916. Ahead of Print .
    1. Jang D.I., Lee A.H., Shin H.Y., Song H.R., Park J.H., Kang T.B., Lee S.R., Yang S.H. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int. J. Mol. Sci. 2021;22:2719. doi: 10.3390/ijms22052719.
    1. Qiao Y.C., Chen Y.L., Pan Y.H., Tian F., Xu Y., Zhang X.X., Zhao H.L. The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. PLoS One. 2017;12:e0176157. doi: 10.1371/journal.pone.0176157.
    1. Wang K., Li F., Cui Y., Cui C., Cao Z., Xu K., Han S., Zhu P., Sun Y. The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between? Mediat. Inflamm. 2019;2019:2987901. doi: 10.1155/2019/2987901.
    1. Ozgur B.A., Cinar S.A., Coskunpinar E., Yilmaz A., Altunkanat D., Deniz G., Gurol A.O., Yilmaz M.T. The role of cytokines and T-bet, GATA3, ROR-γt, and FOXP3 transcription factors of T cell subsets in the natural clinical progression of Type 1 Diabetes. Immunol. Res. 2023 doi: 10.1007/s12026-022-09355-z.
    1. Alkaabi J., Sharma C., Yasin J., Afandi B., Beshyah S.A., Almazrouei R., Alkaabi A., Al Hamad S., Ahmed L.A., Beiram R., et al. Relationship between lipid profile, inflammatory and endothelial dysfunction biomarkers, and type 1 diabetes mellitus: A case-control study. Am. J. Transl. Res. 2022;14:4838–4847.
    1. Lechleitner M., Koch T., Herold M., Dzien A., Hoppichler F. Tumour necrosis factor-alpha plasma level in patients with type 1 diabetes mellitus and its association with glycaemic control and cardiovascular risk factors. J. Intern. Med. 2000;248:67–76. doi: 10.1046/j.1365-2796.2000.00705.x.
    1. Arnold S.V., de Lemos J.A., Zheng L., Rosenson R.S., Ballantyne C.M., Alam S., Bhatt D.L., Cannon C.P., Kosiborod M. Use of optimal medical therapy in patients with diabetes and atherosclerotic cardiovascular disease: Insights from a prospective longitudinal cohort study. Diabetes Obes. Metab. 2023 doi: 10.1111/dom.15032.
    1. Dallavalasa S., Tulimilli S.V., Prakash J., Ramachandra R., Madhunapantula S.V., Veeranna R.P. COVID-19: Diabetes Perspective&mdash;Pathophysiology and Management. Pathogens. 2023;12:184.
    1. Conlon K.C., Miljkovic M.D., Waldmann T.A. Cytokines in the Treatment of Cancer. J. Interferon Cytokine Res. 2019;39:6–21. doi: 10.1089/jir.2018.0019.
    1. Starosz A., Jamiołkowska-Sztabkowska M., Głowińska-Olszewska B., Moniuszko M., Bossowski A., Grubczak K. Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children. Front. Immunol. 2022;13:958430. doi: 10.3389/fimmu.2022.958430.
    1. Besser R.E.J., Bell K.J., Couper J.J., Ziegler A.-G., Wherrett D.K., Knip M., Speake C., Casteels K., Driscoll K.A., Jacobsen L., et al. ISPAD Clinical Practice Consensus Guidelines 2022: Stages of type 1 diabetes in children and adolescents. Pediatr. Diabetes. 2022;23:1175–1187. doi: 10.1111/pedi.13410.
    1. Chiang J.L., Maahs D.M., Garvey K.C., Hood K.K., Laffel L.M., Weinzimer S.A., Wolfsdorf J.I., Schatz D. Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association. Diabetes Care. 2018;41:2026–2044. doi: 10.2337/dci18-0023.
    1. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262.
    1. Wolfsdorf J.I., Glaser N., Agus M., Fritsch M., Hanas R., Rewers A., Sperling M.A., Codner E. ISPAD Clinical Practice Consensus Guidelines 2018: Diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr. Diabetes. 2018;19:155–177. doi: 10.1111/pedi.12701.
    1. DiMeglio L.A., Acerini C.L., Codner E., Craig M.E., Hofer S.E., Pillay K., Maahs D.M. ISPAD Clinical Practice Consensus Guidelines 2018: Glycemic control targets and glucose monitoring for children, adolescents, and young adults with diabetes. Pediatr. Diabetes. 2018;19:105–114. doi: 10.1111/pedi.12737.
    1. Nunes R. Citocinas de resposta Th1 e Th2 e diabetes mellitus tipo 1. Th1 Th2 Response Cytokins Type 1 Diabetes Mellit. 2017;49:359–364. doi: 10.21877/2448-3877.201700596.
    1. Ding J.T., Yang K.P., Lin K.L., Cao Y.K., Zou F. Mechanisms and therapeutic strategies of immune checkpoint molecules and regulators in type 1 diabetes. Front. Endocrinol. 2022;13:1090842. doi: 10.3389/fendo.2022.1090842.
    1. Ghoneum M.H., Gimzewski J.K., Ghoneum A.D., Agrawal S. Potential role of MRN-100, an iron-based compound, in upregulating production of cytokine IL-10 in human dendritic cells to promote an anti-inflammatory response in vitro. Int. J. Immunopathol. Pharmacol. 2019;33:2058738419844932. doi: 10.1177/2058738419844932.
    1. Seyfarth J., Fortsch K., Ahlert H., Laws H.J., Karges B., Deenen R., Kohrer K., Mayatepek E., Meissner T., Jacobsen M. Dominant TNFalpha and impaired IL-2 cytokine profiles of CD4(+) T cells from children with type-1 diabetes. Immunol. Cell Biol. 2017;95:630–639. doi: 10.1038/icb.2017.24.
    1. Cheng J., Zhong T., Yan X., Xie Y.T., He B.B., Li X., Zhou Z.G. The relation between residual β-cell function and autoimmune status in long-term type 1 diabetes patients. Zhonghua Yi Xue Za Zhi. 2022;102:1209–1215. doi: 10.3760/cma.j.cn112137-20211019-02309.
    1. Boks M.A., Kager-Groenland J.R., Mousset C.M., van Ham S.M., ten Brinke A. Inhibition of TNF receptor signaling by anti-TNFalpha biologicals primes naive CD4(+) T cells towards IL-10(+) T cells with a regulatory phenotype and function. Clin. Immunol. 2014;151:136–145. doi: 10.1016/j.clim.2014.02.008.
    1. Boks M.A., Kager-Groenland J.R., van Ham S.M., ten Brinke A. IL-10/IFNgamma co-expressing CD4(+) T cells induced by IL-10 DC display a regulatory gene profile and downmodulate T cell responses. Clin. Immunol. 2016;162:91–99. doi: 10.1016/j.clim.2015.11.011.
    1. Kyriacou A., Melson E., Chen W., Kempegowda P. Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus? Clin. Med. 2020;20:417–423. doi: 10.7861/clinmed.2020-0054.
    1. Cnop M., Welsh N., Jonas J.C., Jörns A., Lenzen S., Eizirik D.L. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: Many differences, few similarities. Diabetes. 2005;54:S97–S107. doi: 10.2337/diabetes.54.suppl_2.S97.
    1. Lu J., Liu J., Li L., Lan Y., Liang Y. Cytokines in type 1 diabetes: Mechanisms of action and immunotherapeutic targets. Clin. Transl. Immunol. 2020;9:e1122. doi: 10.1002/cti2.1122.
    1. Rickels M.R., Evans-Molina C., Bahnson H.T., Ylescupidez A., Nadeau K.J., Hao W., Clements M.A., Sherr J.L., Pratley R.E., Hannon T.S., et al. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J. Clin. Invest. 2020;130:1850–1862. doi: 10.1172/JCI134057.
    1. Robert S., Gysemans C., Takiishi T., Korf H., Spagnuolo I., Sebastiani G., Van Huynegem K., Steidler L., Caluwaerts S., Demetter P., et al. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes. 2014;63:2876–2887. doi: 10.2337/db13-1236.
    1. Li C., Zhang L., Chen Y., Lin X., Li T. Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice. Exp. Ther. Med. 2016;11:1625–1632. doi: 10.3892/etm.2016.3169.
    1. Huang J., Tan Q., Tai N., Pearson J.A., Li Y., Chao C., Zhang L., Peng J., Xing Y., Zhang L., et al. IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice. Front. Immunol. 2021;12:702955. doi: 10.3389/fimmu.2021.702955.
    1. Rapoport M.J., Mor A., Vardi P., Ramot Y., Winker R., Hindi A., Bistritzer T. Decreased secretion of Th2 cytokines precedes Up-regulated and delayed secretion of Th1 cytokines in activated peripheral blood mononuclear cells from patients with insulin-dependent diabetes mellitus. J. Autoimmun. 1998;11:635–642. doi: 10.1006/jaut.1998.0240.
    1. Kleffel S., Vergani A., Tezza S., Ben Nasr M., Niewczas M.A., Wong S., Bassi R., D'Addio F., Schatton T., Abdi R., et al. Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens. Diabetes. 2015;64:158–171. doi: 10.2337/db13-1639.
    1. Wogensen L., Lee M.S., Sarvetnick N. Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice. J. Exp. Med. 1994;179:1379–1384. doi: 10.1084/jem.179.4.1379.
    1. Moritani M., Yoshimoto K., Tashiro F., Hashimoto C., Miyazaki J., Ii S., Kudo E., Iwahana H., Hayashi Y., Sano T., et al. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int. Immunol. 1994;6:1927–1936. doi: 10.1093/intimm/6.12.1927.
    1. Rabinovitch A., Suarez-Pinzon W.L. Roles of cytokines in the pathogenesis and therapy of type 1 diabetes. Cell Biochem. Biophys. 2007;48:159–163. doi: 10.1007/s12013-007-0029-2.
    1. Nikolic T., Suwandi J.S., Wesselius J., Laban S., Joosten A.M., Sonneveld P., Mul D., Aanstoot H.J., Kaddis J.S., Zwaginga J.J., et al. Tolerogenic dendritic cells pulsed with islet antigen induce long-term reduction in T-cell autoreactivity in type 1 diabetes patients. Front. Immunol. 2022;13:1054968. doi: 10.3389/fimmu.2022.1054968.
    1. Iglesias M., Arun A., Chicco M., Lam B., Talbot C.C., Jr., Ivanova V., Lee W.P.A., Brandacher G., Raimondi G. Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice. Front. Immunol. 2018;9:1565. doi: 10.3389/fimmu.2018.01565.
    1. Germini D.E., Franco M.I.F., Fonseca F.L.A., de Sousa Gehrke F., da Costa Aguiar Alves Reis B., Cardili L., Oshima C.T.F., Theodoro T.R., Waisberg J. Association of expression of inflammatory response genes and DNA repair genes in colorectal carcinoma. Tumour Biol. 2019;42:1010428319843042. doi: 10.1177/1010428319843042.
    1. Quiros M., Nishio H., Neumann P.A., Siuda D., Brazil J.C., Azcutia V., Hilgarth R., O'Leary M.N., Garcia-Hernandez V., Leoni G., et al. Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J. Clin. Investig. 2017;127:3510–3520. doi: 10.1172/JCI90229.
    1. Ramalho T., Filgueiras L., Silva-Jr I.A., Pessoa A.F.M., Jancar S. Impaired wound healing in type 1 diabetes is dependent on 5-lipoxygenase products. Sci. Rep. 2018;8:14164. doi: 10.1038/s41598-018-32589-7.
    1. Green E.A., Flavell R.A. The temporal importance of TNFalpha expression in the development of diabetes. Immunity. 2000;12:459–469. doi: 10.1016/S1074-7613(00)80198-3.
    1. He J., Haskins K. Pathogenicity of T helper 2 T-cell clones from T-cell receptor transgenic non-obese diabetic mice is determined by tumour necrosis factor-alpha. Immunology. 2008;123:108–117. doi: 10.1111/j.1365-2567.2007.02715.x.
    1. Koulmanda M., Bhasin M., Awdeh Z., Qipo A., Fan Z., Hanidziar D., Putheti P., Shi H., Csizuadia E., Libermann T.A., et al. The role of TNF-alpha in mice with type 1- and 2- diabetes. PLoS One. 2012;7:e33254. doi: 10.1371/journal.pone.0033254.
    1. Lee L.F., Xu B., Michie S.A., Beilhack G.F., Warganich T., Turley S., McDevitt H.O. The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: Analysis of dendritic cell maturation. Proc. Natl. Acad. Sci. USA. 2005;102:15995–16000. doi: 10.1073/pnas.0508122102.
    1. Christen U., Wolfe T., Möhrle U., Hughes A.C., Rodrigo E., Green E.A., Flavell R.A., von Herrath M.G. A dual role for TNF-alpha in type 1 diabetes: Islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis. J. Immunol. 2001;166:7023–7032. doi: 10.4049/jimmunol.166.12.7023.
    1. Yang X.D., Tisch R., Singer S.M., Cao Z.A., Liblau R.S., Schreiber R.D., McDevitt H.O. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 1994;180:995–1004. doi: 10.1084/jem.180.3.995.
    1. Wang G., Yan Y., Xu N., Yin D., Hui Y. Treatment of type 1 diabetes by regulatory T-cell infusion via regulating the expression of inflammatory cytokines. J. Cell. Biochem. 2019;120:19338–19344. doi: 10.1002/jcb.27875.
    1. Hamouda L., Miliani M., Hadjidj Z., Messali R., Aribi M. Rituximab Treatment Modulates the Release of Hydrogen Peroxide and the Production of Pro-inflammatory Cytokines by Monocyte at the Onset of Type 1 Diabetes. Endocr. Metab. Immune Disord. Drug Targets. 2019;19:643–655. doi: 10.2174/1871530319666190215153213.
    1. Dib S.A. Heterogeneity of type 1 diabetes mellitus. Arq. Bras. de Endocrinol. Metabol. 2008;52:205–218. doi: 10.1590/S0004-27302008000200008.
    1. Couper J.J., Haller M.J., Greenbaum C.J., Ziegler A.G., Wherrett D.K., Knip M., Craig M.E. ISPAD Clinical Practice Consensus Guidelines 2018: Stages of type 1 diabetes in children and adolescents. Pediatr. Diabetes. 2018;19:20–27. doi: 10.1111/pedi.12734.
    1. Bergamin C.S., Dib S.A. Enterovirus and type 1 diabetes: What is the matter? World J. Diabetes. 2015;6:828–839. doi: 10.4239/wjd.v6.i6.828.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe