Effect of the Serum Level of Interleukin-6 and Interleukin-10 on Chemotherapy in Acute Myeloid Leukemia Iraqi Patients
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Abstract
Background: Acute myeloid leukemia (AML), a cancer of the myeloid line of blood cells, It is characterized by malignant clonal proliferation and differentiation of immature myeloid progenitor cells that differentiate into malignant myeloblasts which cannot function like normal blood cells. Normally, cytokines are secreted by different types of cells to regulate the immune response, but in AML patients, cytokines can be produced by both leukemic blasts and immune system cells and their role in the pathogenesis is not clear .Blood cells and their marrow based progenitors are exquisitely responsive to their environment, and cytokines are an essential part of it. The overexpression of cytokines in leukemia patients declines in complete remission suggesting that these events are dependent on AML activity. Aim of the study is to determine the serum levels of IL-6, IL-10 in newly diagnosed, under treatment and relapsed acute myeloid leukemia Iraqi patients and show their relation to response to chemotherapy and used as a prognostic markers in the evaluation of the therapy making them highly applicable to routine clinical laboratories.
Methods: Serum levels of IL-6, IL-10 were estimated by using ELISA kit, in 120 patients with AML, That divided into 40 patients for each group (newly diagnosed, under treatment and relapsed), depending on the stages of the patients with chemotherapy, from February 2022 to April 2023 from Baghdad Teaching Hospital, Baghdad, Iraq. Forty healthy controls were also enrolled in this study.
Results: IL-6 and IL-10 levels were significantly higher in newly diagnosed and relapsed patients with AML than in control group and their levels decreased when patients responded to chemotherapy.
Conclusion: The current study showed that the serum concentrations of IL-6 and IL-10 in AML patients increased before chemotherapy and began to decreased after therapy. These results may be used as a prognostic markers for the success of chemotherapy and could offer an interesting approach for treatment of AML.
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References
I. Khan M, Din M, Naeem Z, Sajid Z, Khan D, Amjad MD, Zeb A, Anwar F, Akhtar M, Noreen S. Insights into Acute Myeloid Leukemia: Critical Analysis on its Wide Aspects. Abasyn Journal of Life Sciences 2020; 3(2): 1-9.
II. Smith, M., Barnett, M., Bassan, R., Gatta, G. ; Tondini, C. and Kern, W.( 2004) .Adult acute myeloid leukaemia. Crit Rev Oncol Hematol. 50(3): 197-222.
III. DOHNER H., ESTEY E.H., AMADORI S., APPELBAUM F.R., BUCHNER T., BURNETT A.K., et al.: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia Net. Blood, 115: 453- 74, 2010.
IV. ESTEY E.H.: Acute myeloid leukemia: Update on diag-nosis, risk stratification, and management. Am. J. Hema-tol., 87: 89-99, 2012.
V. PANJU A.H., DANESH A., MINDEN M.D., KELVIN D.J. and ALIBHAI S.M.: Associations between quality of life, fatigue, and cytokine levels in patients aged 50+ with acute myeloid leukemia. Support Care Cancer, 17: 539-46, 2009.
VI. TSIMBERIDOU A.M., ESTEY E., WEN S., PIERCE S., KANTARJIAN H., ALBITAR M. and KURZROCK R.: The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelo-dysplastic syndromes. Cancer, 113 (7): 1605-13, 2008.
VII. KIMURA A., KISHIMOTO T.: IL-6: Regulator of Treg/ Th17 balance. Eur. J. Immunol., 40: 1830-5, 2010.
VIII. STENVINKEL P., KETTELER M., JOHNSON R.J., LINDHOLM B., PECOITS-FILHO R., RIELLA M., et al.: IL-10, IL-6, and TNF-alpha: Central factors in the altered cytokine network of uremia-the good, the bad, and the ugly. Kidney Int., 67: 1216-33, 2005.
IX. Alexandrakis MG, Passam FH, Kyriakou DS, Christophoridou AV, Perisinakis K, Hatzivasili A, et al. Serum level of interleukin-16 in multiple myeloma patients and its relationship to disease activity. Am J Hematol 2004;75:101–6.
X. Santer FR, Malinowska K, Culig Z, Cavarretta IT. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr-relat cancer 2010;17:241–53.
XI. Suchi K, Fujiwara H, Okamura S, Okamura H, Umehara S, Todo M, et al. Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. Anticancer Res 2011;31: 67–75.
XII. SHENGHUI Z., YIXIANG H., JIANBO W., et al.: Elevated frequencies of CD4(+) CD25(+) CD127(lo) regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int. J. Cancer, 129: 1373-81, 2011.
XIII. BENDALL L.: Chemokines and their receptors in disease. Histol. Histopathol., 20 (3): 907-26, 2005.
XIV. WU S., GESSNER R., TAUBE T., VON STACKELBERG A., HENZE G. and SEEGER K.: Expression of interleukin-10 splicing variants is a positive prognostic feature in relapsed childhood acute lymphoblastic leukemia. J. Clin. Oncol., 23: 3038-42, 2005.
XV. Afzal, N., Tahir, R., Jahan, S.(2012). Cytokines: an ever expanding area. Review/ Biological and Biomedical Reports . 2(1): 37-43.
XVI. PANTELI K.E., HATZIMICHAEL E.C., BOURANTA P.K., KATSARAKI A., SEFERIADIS K., STEBBING J., et al.: Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myelopro-liferative diseases. Brit. J. Haematol., 130: 709-15, 2005.
XVII. COUSSENS L.M. and WERB Z.: Inflammation and cancer. Nature, 420 (6917): 860-7, 2002.
XVIII. WU H.A.O., PENG L.I., SHAO A., JINGJING M.A., MIN J.I., et al.: Aberrant expression of Treg associated cytokine IL-35 along with IL-10 and TGF-beta in acute myeloid leukemia, 1119-23, 2012.
XIX. Musuraca G, De Matteis S, Napolitano R, Papayannidis C, Guadagnuolo V, Fabbri F, et al. IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia. J Transl Med (2015) 13:229.
XX. HSIEH C.L., CHEN D.S. and HWANg L.H.: Tumor-induced immunosuppression: A barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine. Hum. Gene Ther., 11: 681-92, 2000.
XXI. YANG Y., ZHANG W.G., QIAO Y.C., et al.: The quantitate method of serum IFN-y and IL-10 in AML patients. Chin. J. Hematol., 23: 371-2, 2002.
XXII. YAO CH.J., DU W., CHEN H.B., XIAO S.H., WANG CH.H. and FAN ZI LI: Associations of IL-10 Gene Pol-ymorphisms with Acute Myeloid Leukemia in Hunan, China. Asian Pacific Journal Cancer Prev., Vol. 14 (4): 2439-42, 2013
XXIII. Szlosarek P , Kellie A , Frances R. Tumour necrosis factor-alpha as a tumour promoter . Eur J Cancer 2006 Apr;42(6):745-50.
XXIV. Reuter S, Subash C. , Madan M. , and Bharat B. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 2010 Dec 1; 49(11): 1603–1616.
XXV. Yulan, Li., Guili, Zhang., Na, Wang., Miaomiao, Mi., Yu Xin Huihui, Jiang., Chengming Su. (2021). Cancer Management and Research:13.
XXVI. Sun YX, Kong HL, Liu CF, Yu S, Tian T, Ma DX, et al. The imbalanced profile and clinical significance of T helper associated cytokines in bone marrow microenvironment of the patients with acute myeloid leukemia. Hum Immunol (2014) 75(2):113–8.
XXVII. Hu R, Ling X, Yang T, et al. Cytokine levels in patients with non-M3 myeloid leukemia are key indicators of how well the disease responds to chemotherapy.. Research Square; 2023. DOI: 10.21203/rs.3.rs-2541753/v1.
XXVIII. Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Banas H, et al. Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine (2013) 61(3):885–91.
XXIX. Park, H.H., Kim, M., Lee, B.-H. , Lim, J., Kim, Y., Lee, E. J., Min, W. S., Kang, C. S., Kim, W. I., Shim ,S. I. and Han, K.(2006). Intracellular IL-4, IL-10, and IFN-g Levels of Leukemic Cells and Bone Marrow T Cells in Acute Leukemia. Annals of Clinical & Laboratory Science.36(1):7_15 .
XXX. Ghasoun M. Evaluation of Immunological Parameters Associated with Acute Myeloid Leukemia in a Sample of Iraqi Patients. Phd. Thesis. University of Baghdad; 2013.
XXXI. Panoskaltsis, N., Reid, C.D. and Knight, S.C.(2003). Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia. Leukemia; 17(4): 716-30.
XXXII. Abd el-Hafez
XXXIII. MOCELLIN S., WANG E. and MARINCOLA F.M.: Cytokines and Immune Response in the Tumor Microen-vironment. Journal of Immunotherapy: Review, Vol. 24- Issue 5-pp. 392-407, 2001.
XXXIV. Sato, T., Terai, M., Tamura, Y., Alexeev, V., Mastrangelo, M.J. and Sel-van, S.R.( 2011).Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol. Res. 51(2-3): 170-182.
XXXV. Sakamoto, T., Saito, H., Tatebe, S., Tsujitani ,S., Ozaki, M., Ito, H. and Ikeguchi, M.( 2006). Interleukin-10 expression significantly correlates with minor CD8+ T-cell infiltration and high microvessel density in patients with gastric cancer. Int. J. Cancer.118(8): 1909-1914.
XXXVI. Huber,S. O'Keeffea, M. and Luftb, T.(2011).Th17 cells express interleukine-10 receptor and are controlled by FOX3¯ and FOX3+ regulatory CD4+ cells in an interleukine-10 _dependent manner.Immunity.34(4):554-65.
XXXVII. Ersvaer,E.; Liseth,K.; Skavland,J.; Gjertsen,B.T. and Bruserud,O.(2010). Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells. BMC Immunology. 11(9):38-50.
XXXVIII. ABD EL-MAKSOUD N., RAGAB M.H., ABD EL-LATIF M.M. and ABDALLA S.H.: Prognostic Impact of Elevated Serum Hyulronic Acid, Ferritin and Interleukin-6 in Patients with Acute Myeloid Leukemia. Journal of Amer-ican Science, 532-41. ISSN: 1545-1003, 2002.
XXXIX. DAWOOD D.S.: Assessment of IL-6 Serum Level in Patients With Acute Myeloid Leukemia. Iraqi Journal of Cancer and Medical Genetics, Vol. 4, No. 1, PP. 22-8. 2011.
XL. WU C., WANG S., WANG F., CHEN Q., PENG S., ZHANG Y., QIAN J., JIN J. and XU H.: Increased fre-quencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. British Society for Immunology, Clinical and Experimental Immunology, 158: 199-204, 2009.
XLI. FREDLY H., REIKVAM H., GJERTSEN B.T. and BRUSERUD O.: Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: Serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment. Am. J. Hematol., 87: 368, 2012.
XLII. TIAN T., YU S.H., WANG M., YUAN C., ZHANG H., JI C.H. and MA D.: Aberrant T Helper 17 Cells and Related Cytokines in Bone Marrow Microenvironment of Patients with Acute Myeloid Leukemia. Hindawi Publishing Cor-poration, Clinical and Developmental Immunology, Vol. 2013, Article ID 915873, 10 pages. http://dx.doi.org/ 10.1155/2013/915873, 2013.
XLIII. AL-Khateeb, S. ., Thair Tahir, N., & Al-bayati, A. A. H. . (2022). Immune and inflammatory cytokines profile in Iraqi patients with acute and chronic myeloid leukemia. Biomedicine, 42(2), 262–267.
XLIV. Stevens AM, Miller JM, Munoz JO, Gaikwad AS, Redell MS. Interleukin-6 levels predict event-free survival in pediatric AML and suggest a mechanism of chemotherapy resistance. Blood Adv (2017) 1(18):1387–97.
XLV. Kadhum M. S., Abdullah A. R. and Shabeeb Z. A., 2022 Estimation of the IL-6 serum level in the Iraqi newly diagnosed AML patients Teikyo Medical Journal, 45 (1),
XLVI. ALIZADEH S.H., BOHLOLI S.H., ABEDI A., MOUSAVI S.H., DARGAHI H., JAFARZADEH B., HAMRANG N. and IMANI A.: Investigation of Leptin, Leukemia Inhib-itory Factor (LIF), and IL-6 Serum Levels in Myeloid Leukemia. Iranian Journal of Blood and Cancer, Vol. 2, No. 4, IJBC 3: 95-100, 2011.
XLVII. Schuringa JJ, Wierenga AT, Kruijer W, Vellenga E. Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood. 2000;95(12):3765-3770.
XLVIII. Gao SP, Mark KG, Leslie K, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117(12):3846-3856.
XLIX. Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117(12):3988-4002.
L. Matthes T, Manfroi B, Zeller A, Dunand-Sauthier I, Bogen B, Huard B. Autocrine amplification of immature myeloid cells by IL-6 in multiple myelomainfiltrated bone marrow. Leukemia. 2015;29(9):1882-1890.
LI. Reikvam H, Brenner AK, Hagen KM, et al. The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells. Stem Cell Res (Amst). 2015;15(3):530-541.
LII. Zhang Y, Guo H, Zhang Z, Lu W, Zhu J, Shi J. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia. Exp Cell Res (2022) 415(1):113112.
LIII. Long X, Yu Y, Perlaky L, Man TK, Redell MS. Stromal CYR61 confers resistance to mitoxantrone via spleen tyrosine kinase activation in human acute myeloid leukaemia. Br J Haematol. 2015;170(5):704-718.
LIV. Stevens AM, Ruiz MJ, Gerbing RB, Alonzo TA, Gamis AS, Redell MS. Ligand-induced STAT3 signaling increases at relapse and is associated with outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Haematologica. 2015;100(12):e496-e500.
LV. Hou D, Wang B, You R, Wang X, Liu J, Zhan W, et al. Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis. Ann Transl Med (2020) 8(21):1346. doi: 10.21037/atm-20-3191