Изменение экспрессии негативного регулятора транскрипции генов SOCS1 при нарушениях метаболизма у пациентов с бронхиальной астмой
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Sorokina LN, Lim VV, Mineev VN, Nyoma MA, Lalayeva TM. Change in the expression of gene transcription negative regulator SOCS1 in the patients with bronchial asthma and metabolic disorders. Terapevticheskii Arkhiv (Ter. Arkh). 2021; 93 (3): 255–259. DOI: 10.26442/00403660.2021.03.200636
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Материалы и методы. Обследованы 113 человек: 63 – с аллергической БА (АБА), 50 – с неаллергическим вариантом болезни (НАБА). Экспрессию мРНК SOCS1 оценивали путем проведения полимеразной цепной реакции с обратной транскрипцией (англ. RT-PCR). Экспрессию белка SOCS1 исследовали методом иммуноблоттинга. Определяли уровни цитокинов по стандартному протоколу на проточном флюориметре (Biо-Plex).
Результаты. Выявлено разнонаправленное и значимое изменение экспрессии матричной РНК SOCS1 при увеличении индекса массы тела более 25 (больше нормы), НАБА и АБА. Наличие ряда положительных корреляционных связей между экспрессией мРНК SOCS1 и индексом массы тела указывает на регулирующую роль SOCS1 в лептиновом сигнальном пути. Варианты корреляционных связей при АБА и НАБА различны, что может указывать на возможное существование особенностей в патогенезе данных вариантов заболевания.
Заключение. Полученные результаты позволяют рассматривать сложные нарушения регуляции, возникающие на различных уровнях клеточной сигнализации, с точки зрения полифункциональности регулятора SOCS1. Данный регулятор обеспечивает комплексный контроль цитокиновой сигнализации в различных сигнальных путях при БА в сочетании с нарушениями метаболизма.
Ключевые слова: бронхиальная астма, сахарный диабет, система SOCS-белков, SOCS1, лептин, мононуклеарные клетки
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Aim. Comprehensive study of the negative regulation components of cell signaling in the bronchial asthma (BA) patients with metabolic disorders.
Materials and methods. 113 people were examined: 63 patients with allergic BA (ABA), 50 patients with a non-allergic variant of the disease (NABA). SOCS1 mRNA expression was evaluated by reverse transcription PCR (RT-PCR). SOCS1 protein expression was investigated by immunoblotting. The determination of cytokine levels was carried out according to the standard protocol on a Bio-Plex flow fluorimeter.
Results. A significant and multidirectional change in the expression of SOCS1 mRNA was found at a body mass index >25 (greater than normal) in ABA and NABA. The positive correlations between SOCS1 mRNA expression and body mass index indicate the regulatory role of SOCS1 in leptin signaling. The spectra of correlations in ABA and NABA are different, it indicates the probable existence of specificity in the pathogenesis of these variants of the diseases.
Conclusion. The obtained data allow us to consider the complexity of regulation disorders occurring at different levels of cell signaling. The multifunctionality of the SOCS1 regulator provides complex control of cytokine signaling simultaneously in different signaling pathways in the BA with metabolic disorders.
Keywords: bronchial asthma, diabetes mellitus, SOCS-protein system, SOCS1, leptin, mononuclear cells
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13. Naka T, Tsutsui H, Fujimoto M, et al. SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN- γ and IL-4 signaling in vivo. Immunity. 2001;14:535-45. PMID: 11371356
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15. Motta M, Accornero P, Baratta M. Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. Regul Pept. 2004;121(1-3):163-70. doi: 10.1016/j.regpep.2004.05.002
16. Fazeli M, Zarkesh-Esfahani H, Wu Z, et al. Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods. 2006; 312(1-2):190-200. doi:10.1016/j.jim.2006.03.011
17. Ogbera A, Azenabor A, Ogundahunsi OA, et al. Cytokines, Type 2 DM and the Metabolic Syndrome. Nig Q J Hosp Med. 2013;23(4):318-22. PMID: 27276762
18. Mori H, Okubo M, Okamura M, et al. Abnormalities of pulmonary function in patients with noninsulin-dependent diabetes mellitus. Intern Med. 1992;31(2):189-93. PMID: 1600265
19. Cheng A, Uetani N, Simoncic PD, et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase-1B. Dev Cell. 2002;2:497-503. PMID: 11970899
20. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24(12):5434-46.
doi: 10.1128/MCB.24.12.5434-5446.2004
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1. Mineev VN, Sorokina LN. The expression STAT6 in peripheral blood lymphocytes in patients with allergic bronchial asthma. Medical Immunology. 2007;9(4-5):405-11 (In Russ.) doi: 10.15789/1563-0625-2007-4-5-405-410
2. Mineev VN, Sorokina LN, Trofimov VI. The fundamental and clinical aspects of the JAK-STAT signaling. Saint Petersburg: BBM, 2010 (In Russ.)
3. Yoshimura А, Suzuki M, Sakaguchi R, et al. SOCS, inflammation, and autoimmunity. Front Immunol. 2012;3:20. eCollection 2012. doi: 10.3389/fimmu.2012.00020
4. Nicholson SE, Metcalf D, Sprigg NS, et al. Suppressor of cytokine signaling (SOCS)-5 is a potential negative regulator of epidermal growth factor signaling. Proc Natl Acad Sci U S A. 2005;102(7):2328-33. doi: 10.1073/pnas.0409675102
5. Kasayama S, Tanemura M, Koga M, et al. Asthma is an independent risk for elevation of plasma C-reactive protein levels. Clin Chim Acta. 2009;399(1-2):79-82. doi: 10.1016/j.cca.2008.09.013
6. Singh S, Bodas M, Bhatraju NK, et al. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol. 2016;310(9):837-45. doi: 10.1152/ajplung.00091.2015
7. Brownlee М. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995;46:223-34. doi: 10.1146/annurev.med.46.1.223
8. Sorokina LN, Ivanov VA, Lim VV, et al. Cytokine profile features in the patient with nonallergic bronchial asthma with co-existing type 2 diabetes mellitus. Medical Immunology. 2017;19(3):313-8 (In Russ.) doi: 10.15789/1563-0625-2017-3-313-318
9. Sorokina LN, Mineev VN, Lim VV. Role of negative regulators of SOCS1, SOCS3, and SOCS5 gene transcription in the negative cell signaling regulation system in asthma. Terapevticheskii Arkhiv (Ter. Arkh). 2017;89(3):43-7 (In Russ.)
doi: 10.17116/terarkh201789343-47
10. Mineev VN, Lim VV, Nyoma MA, Trofimov VI. The expression of SOCS proteins in negative regulation of JAK-STAT signaling. Cytokiny i vospalenie. 2012;11(2):23-7 (In Russ.)
11. Mineev VN, Sorokina LN, Berestovskaia VS, et al. Plasma leptin level in patients with bronchial asthma. Klinicheskaia meditsina. 2009;87(7):33-7 (In Russ.)
12. Fujimoto M, Naka T. Regulation of cytokine signaling by SOCS family molecules. Trends Immunology. 2003:24(12):659-66. PMID: 14644140
13. Naka T, Tsutsui H, Fujimoto M, et al. SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN- γ and IL-4 signaling in vivo. Immunity. 2001;14:535-45. PMID: 11371356
14. Davey GM, Heath WR, Starr R. SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. J Tissue Antigens. 2006;67(1):1-9. doi: 10.1111/j.1399-0039.2005.00532.x
15. Motta M, Accornero P, Baratta M. Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. Regul Pept. 2004;121(1-3):163-70. doi: 10.1016/j.regpep.2004.05.002
16. Fazeli M, Zarkesh-Esfahani H, Wu Z, et al. Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods. 2006; 312(1-2):190-200. doi:10.1016/j.jim.2006.03.011
17. Ogbera A, Azenabor A, Ogundahunsi OA, et al. Cytokines, Type 2 DM and the Metabolic Syndrome. Nig Q J Hosp Med. 2013;23(4):318-22. PMID: 27276762
18. Mori H, Okubo M, Okamura M, et al. Abnormalities of pulmonary function in patients with noninsulin-dependent diabetes mellitus. Intern Med. 1992;31(2):189-93. PMID: 1600265
19. Cheng A, Uetani N, Simoncic PD, et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase-1B. Dev Cell. 2002;2:497-503. PMID: 11970899
20. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24(12):5434-46.
doi: 10.1128/MCB.24.12.5434-5446.2004
ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, Санкт-Петербург, Россия
*limvaleria@mail.ru
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Lada N. Sorokina, Valeria V. Lim*, Valery N. Mineev, Mikhail A. Nyoma, Tatiana M. Lalayeva
Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russia
*limvaleria@mail.ru