The Interplay between Hepcidin, Il-6, and NF-ΚB in Transfusion-Dependent Thalassemia-Β Patients

Assha Luthfianie Alifah; Lantip Rujito; Wahyu Siswandari

doi:10.37287/ijghr.v7i2.5630

Assha Luthfianie Alifah Universitas Jenderal Soedirman https://orcid.org/0009-0003-6495-1761
Lantip Rujito Universitas Jenderal Soedirman https://orcid.org/0000-0001-6595-3265
Wahyu Siswandari Universitas Jenderal Soedirman https://orcid.org/0000-0003-1836-8367

DOI: https://doi.org/10.37287/ijghr.v7i2.5630

Keywords: blood transfusion, hepcidin, IL-6, NFΚB, thalassemia

Abstract

Hepcidin, a key regulator of iron metabolism, interacts with inflammatory cytokines like IL-6 and transcription factors such as NF-κB, which play crucial roles in the body's response to inflammation and iron homeostasis especially in transfusion-dependent Thalassemia-β patient. Their interplay in transfusion-dependent thalassemia-β patients, particularly in the context of iron chelation therapy, remains underexplored. Understanding these dynamics could provide insights into optimizing treatment strategies for better patient outcomes. Objective: Determine the relationship between hepcidin levels and IL-6 and NFκB in β-thalassemia sufferers who underwent blood transfusions and determine the effect of the type of iron chelation, and the regularity of iron chelation consumption with the relationship between hepcidin, IL-6 and NFκB levels in β-thalassemia sufferers who underwent transfusions blood. Method: A cross-sectional, quantitative correlation study involving transfusion-dependent thalassemia-β patients was conducted. Serum levels of hepcidin, IL-6, and NF-κB were measured, and the relationships among these biomarkers were analyzed using Pearson correlation. The impact of iron chelation therapy type and adherence on these relationships was also assessed using stratified statistical analysis. Results: Hepcidin levels with IL-6 were found with p = 0.757. The next analysis is the relationship between Hepcidin levels and NFκB with p = 0.029. Conclusions: The relationship between hepcidin levels and IL-6 did not contribute significantly, while there was a significant relationship between hepcidin levels and NFκB. The relationship was influenced by moderating variables, namely the type of iron chelation and the regularity of iron chelation consumption.

References

Basu, S., Jalodia, K., Ranjan, S., Yeh, J. R. J., Peterson, R. T., & Sachidanandan, C. (2018). Small Molecule Inhibitors of NFkB Reverse Iron Overload and Hepcidin Deregulation in a Zebrafish Model for Hereditary Hemochromatosis Type 3. ACS Chemical Biology, 13(8), 2143–2152. https://doi.org/10.1021/acschembio.8b00317

Camaschella, C., Nai, A., & Silvestri, L. (2020). Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica, 105(2), 260–272. https://doi.org/10.3324/haematol.2019.232124

Cazzola, M., Della Porta, M. G., & Malcovati, L. (2008). Clinical relevance of anemia and transfusion iron overload in myelodysplastic syndromes. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program, 166–175. https://doi.org/10.1182/asheducation-2008.1.166

Chen, W., Wang, X., Huang, L., & Liu, B. O. (2015). Hepcidin in Non-Alcoholic Fatty Liver Disease Regulated by the TLR4/NF-κB Signaling Pathway. Experimental and Therapeutic Medicine, 11(1), 73–76. https://doi.org/10.3892/etm.2015.2873

Eguchi, A., Mochizuki, T., Tsukada, M., Kataoka, K., Hamaguchi, Y., Oguni, S., Nitta, K., & Tsuchiya, K. (2012). Serum hepcidin levels and reticulocyte hemoglobin concentrations as indicators of the iron status of peritoneal dialysis patients. International Journal of Nephrology, 2012. https://doi.org/10.1155/2012/239476

Ehsan, H., Wahab, A., Anwer, F., Iftikhar, R., & Yousaf, M. N. (2020). Prevalence of Transfusion Transmissible Infections in Beta-Thalassemia Major Patients in Pakistan: A Systemic Review. Cureus, 12(8), 15–20. https://doi.org/10.7759/cureus.10070

Han, Y., Huang, W., Meng, H., Zhan, Y., & Hou, J. (2021). Pro‐inflammatory Cytokine Interleukin‐6‐induced Hepcidin, a Key Mediator of Periodontitis‐related Anemia of Inflammation. Journal of Periodontal Research, 56(4), 690–701. https://doi.org/10.1111/jre.12865

Hong, X., Wang, M., Tang, W., Shen, Z., Miao, L., Wu, W., Li, C., Wang, X., Xin, X., & Zhu, Y. Z. (2016). Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation. Antioxidants & Redox Signaling, 24(2), 70–83. https://doi.org/10.1089/ars.2015.6315

Huang, Y., Yu, L., Liu, R., Liu, J., Yang, G., Zhang, X., Liang, Y., & Lai, Y. (2019). Imbalance of Erythropoiesis and Iron Metabolism in Patients With Thalassemia. International Journal of Medical Sciences, 16(2), 302–310. https://doi.org/10.7150/ijms.27829

Indrakanti, D. L., Alvarado, A., Zhang, X., Birmingham, D. J., Hinton, A., & Rovin, B. H. (2017). The interleukin-6-hepcidin-hemoglobin circuit in systemic lupus erythematosus flares. Lupus, 26(2), 200–203. https://doi.org/10.1177/0961203316659153

Kanamori, Y., Murakami, M., Sugiyama, M., Hashimoto, O., Matsui, T., & Funaba, M. (2017). Interleukin-1β (IL-1β) transcriptionally activates hepcidin by inducing CCAAT enhancer-binding protein δ (C/EBPδ) expression in hepatocytes. Journal of Biological Chemistry, 292(24), 10275–10287. https://doi.org/10.1074/jbc.M116.770974

Kementerian Kesehatan Republik Indonesia. (2023). Angka Pembawa Sifat Talasemia Tergolong Tinggi. Kemenkes Ditjen P2P. https://p2p.kemkes.go.id/angka-pembawa-sifat-talasemia-tergolong-tinggi/

Laghari. (2018). Distribution of ABO Blood Groups and Rhesus Factor In ß-Thalassemia Patients at Thalassemia Care Center NawabShah, Pakistan. Sindh University Research Journal -Science Series, 50(001), 123–128. https://doi.org/10.26692/surj/2018.01.0021

Liu, H. Y., Grant, ;, Hopping, C., Uma Vaidyanathan, ;, Ronquillo, Y. C., Phillip, ;, Hoopes, C., & Majid Moshirfar, ; (2019). Diagnosis of Infectious Keratitis. Med Hypothesis Discov Innov Ophthalmol. Discov Innov Ophthalmol, 8(3), 152–155.

Mendonça, V. R. R. de, Souza, L. C. L. de, Garcia, G., Magalhães, B. M. L., Gonçalves, M. S., Lacerda, M. V. G., & Barral‐Netto, M. (2015). Associations Between Hepcidin and Immune Response in Individuals With Hyperbilirubinaemia and Severe Malaria Due to Plasmodium Vivax Infection. Malaria Journal, 14(1). https://doi.org/10.1186/s12936-015-0930-x

Mujiburrahman, H., Santosa, Q., Setyono, J., Roestijawati, N., & Rujito, L. (2023). Investigating the level of Hba1c and insulin level in β-thalassemia patients. Medisains, 21(3), 85. https://doi.org/10.30595/medisains.v21i3.18362

Öztürk, Z., Gümüşlü, S., Yalçın, K., & Küpesiz, A. (2020). Erythropoiesis and Iron Parameters in Transfusion-Dependent and Nontransfusion-Dependent Thalassemias. Journal of Pediatric Hematology/Oncology, 43(5), 186–192. https://doi.org/10.1097/mph.0000000000002046

Paköz, Z. B., Çekiç, C., Arabul, M., Sartaş Yüksel, E., Ipek, S., Vatansever, S., & Ünsal, B. (2015). An evaluation of the correlation between hepcidin serum levels and disease activity in inflammatory bowel disease. Gastroenterology Research and Practice, 2015(January 2013). https://doi.org/10.1155/2015/810942

Parmar, D., Sedai, A., Ankita, K., Lalith, Agarwal, R. K., Hegde, S., Ramaswami, G., Gowda, A., Girija, S., Gujjal, P., Pushpa, H., Dasaratha Ramaiah, J., Karri, C., Jali, S., Tallur, N. R., Shenoy, U. V., Pinto, D., Ramprakash, S., Raghuram, C. P., … Faulkner, L. (2020). Life expectancy and risk factors for early death in patients with severe thalassemia syndromes in South India. Blood Advances, 4(7), 1448–1457. https://doi.org/10.1182/bloodadvances.2019000760

Pasricha, S. R., Frazer, D. M., Bowden, D. K., & Anderson, G. J. (2013). Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with β-thalassemia major: A longitudinal study. Blood, 122(1), 124–133. https://doi.org/10.1182/blood-2012-12-471441

Rajaeefard, A., Hajipour, M., Tabatabaee, H. R., Hassanzadeh, J., Rezaeian, S., Moradi, Z., Sharafi, M., Shafiee, M., Semati, A., Safaei, S., & Soltani, M. (2015). Analysis of survival data in thalassemia patients in Shiraz, Iran. Epidemiology and Health, 37, e2015031. https://doi.org/10.4178/epih/e2015031

Rodriguez, R., Jung, C. L., Gabayan, V., Deng, J. C., Ganz, T., Nemeth, E., & Bulut, Y. (2014). Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infection and Immunity, 82(2), 745–752. https://doi.org/10.1128/IAI.00983-13

Rujito, L. (2019). Talasemia Genetik Dasar dan Pengelolaan Terkini. In UNSOED Press.

Rujito, L., Maritska, Z., & Sofro, A. S. (2023). β Thalassemia Mutation Flow in Indonesia: A Migration Perspective. Thalassemia Reports, 13(4), 253–261. https://doi.org/10.3390/thalassrep13040022

Shimura, M., Yamamoto, M., Fujii, G., Takahashi, M., Komiya, M., Noma, N., Tanuma, S., Yanaka, A., & Mutoh, M. (2012). Novel Compound SK-1009 Suppresses Interleukin-6 Expression Through Modulation of Activation of Nuclear Factor-KappaB Pathway. Biological and Pharmaceutical Bulletin, 35(12), 2186–2191. https://doi.org/10.1248/bpb.b12-00575

Siddique, A., Nelson, J. E., Aouizerat, B. E., Yeh, M. M., & Kowdley, K. V. (2014). Iron Deficiency in Patients With Nonalcoholic Fatty Liver Disease Is Associated With Obesity, Female Gender, and Low Serum Hepcidin. Clinical Gastroenterology and Hepatology, 12(7), 1170–1178. https://doi.org/10.1016/j.cgh.2013.11.017

Teawtrakul, N., Jetsrisuparb, A., Pongudom, S., Sirijerachai, C., Chansung, K., Wanitpongpun, C., & Fucharoen, S. (2018). Epidemiologic study of major complications in adolescent and adult patients with thalassemia in Northeastern Thailand: the E-SAAN study phase I. Hematology, 23(1), 55–60. https://doi.org/10.1080/10245332.2017.1358845

Traivaree, C., Monsereenusorn, C., Rujkijyanont, P., Prasertsin, W., & Boonyawat, B. (2018). Genotype–phenotype correlation among betathalassemia and beta-thalassemia/HbE disease in Thai children: Predictable clinical spectrum using genotypic analysis. Journal of Blood Medicine, 9, 35–41. https://doi.org/10.2147/JBM.S159295

Tubman, V. N., Fung, E. B., Vogiatzi, M., Thompson, A. A., Rogers, Z. R., Neufeld, E. J., & Kwiatkowski, J. L. (2015). Guidelines for the Standard Monitoring of Patients With Thalassemia. Journal of Pediatric Hematology/Oncology, 37(3), e162–e169. https://doi.org/10.1097/mph.0000000000000307

Tuo, Y., Li, Y., Li, Y., Ma, J., Yang, X., Wu, S., Jin, J., & He, Z. (2024). Global, regional, and national burden of thalassemia, 1990–2021: a systematic analysis for the global burden of disease study 2021. EClinicalMedicine, 72(May), 102619. https://doi.org/10.1016/j.eclinm.2024.102619

Ueda, N., & Takasawa, K. (2018). Impact of inflammation on ferritin, hepcidin and the management of iron deficiency anemia in chronic kidney disease. Nutrients, 10(9). https://doi.org/10.3390/nu10091173

Varga, E., Pap, R., Jánosa, G., Sipos, K., & Pandur, E. (2021). IL-6 Regulates Hepcidin Expression via the BMP/SMAD Pathway by Altering BMP6, TMPRSS6 and TfR2 Expressions at Normal and Inflammatory Conditions in BV2 Microglia. Neurochemical Research, 46(5), 1224–1238. https://doi.org/10.1007/s11064-021-03322-0

Wang, L., Trebicka, E., Fu, Y., Ellenbogen, S., Hong, C. C., Babitt, J. L., Lin, H. Y., & Cherayil, B. J. (2012). The Bone Morphogenetic Protein–hepcidin Axis as a Therapeutic Target in Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 18(1), 112–119. https://doi.org/10.1002/ibd.21675

WHO. (2021). Regional Desk Review of Haemoglobinopathies with an Emphasis on Thalassaemia and Accessibility and Availability of Safe Blood and Blood Products as per These Patients’ Requirement in South-East Asia Under Universal Health Coverage.

Wu, S., Zhang, K., Lv, C., Wang, H., Cheng, B., Jin, Y., Chen, Q., Lian, Q., & Fang, X. (2011). Nuclear Factor-ΚB Mediated Lipopolysaccharide-Induced mRNA Expression of Hepcidin in Human Peripheral Blood Leukocytes. Innate Immunity, 18(2), 318–324. https://doi.org/10.1177/1753425911405087

Wu, X., Yung, L. M., Cheng, W. H., Yu, P. B., Babitt, J. L., Lin, H. Y., & Xia, Y. (2012). Hepcidin Regulation by BMP Signaling in Macrophages Is Lipopolysaccharide Dependent. Plos One, 7(9), e44622. https://doi.org/10.1371/journal.pone.0044622

Zhang, F., Zhao, P., Qian, Z. M., & Zhong, M. (2021). Central Nervous System Inflammation Induced by Lipopolysaccharide Up-Regulates Hepatic Hepcidin Expression by Activating the IL-6/JAK2/STAT3 Pathway in Mice. Frontiers in Nutrition, 8. https://doi.org/10.3389/fnut.2021.649640

Zhang, X., & Rovin, B. H. (2010). Hepcidin expression by human monocytes in response to adhesion and pro-inflammatory cytokines. Biochimica et Biophysica Acta - General Subjects, 1800(12), 1262–1267. https://doi.org/10.1016/j.bbagen.2010.08.005

Zughaier, S. M., Alvarez, J. A., Sloan, J. H., Konrad, R. J., & Tangpricha, V. (2014). The Role of Vitamin D in Regulating the Iron-Hepcidin-Ferroportin Axis In monocytes. Journal of Clinical & Translational Endocrinology, 1(1), e19–e25. https://doi.org/10.1016/j.jcte.2014.01.003