ПОЛИМОРФИЗМ ГЕНОВ ПРОВОСПАЛИТЕЛЬНЫХ ЦИТОКИНОВ (TNF, IL6) И ИХ РЕЦЕПТОРОВ (TNFRSF1A, TNFRSF1B, IL6R) И НЕАЛКОГОЛЬНАЯ ЖИРОВАЯ БОЛЕЗНЬ ПЕЧЕНИ

Людмила Владимировна Топчиева; Ирина Валерьевна Курбатова; Ольга Петровна Дуданова; Анастасия Александровна Соколовская; Анастасия Андреевна Шиповская; Lyudmila Topchieva; Irina Kurbatova; Olga Dudanova; Anastasia Sokolovskaya; Anastasia Shipovskaya

doi:10.17076/eb568

ПОЛИМОРФИЗМ ГЕНОВ ПРОВОСПАЛИТЕЛЬНЫХ ЦИТОКИНОВ (TNF, IL6) И ИХ РЕЦЕПТОРОВ (TNFRSF1A, TNFRSF1B, IL6R) И НЕАЛКОГОЛЬНАЯ ЖИРОВАЯ БОЛЕЗНЬ ПЕЧЕНИ

Людмила Владимировна Топчиева, Ирина Валерьевна Курбатова, Ольга Петровна Дуданова, Анастасия Александровна Соколовская, Анастасия Андреевна Шиповская, Lyudmila Topchieva, Irina Kurbatova, Olga Dudanova, Anastasia Sokolovskaya, Anastasia Shipovskaya

Аннотация

Провоспалительные цитокины (фактор некроза опухоли альфа (TNFα) и интерлейкин 6 (IL6)) играют значительную роль в этиологии и патогенезе неалкогольной жировой болезни печени (НАЖБП), поскольку способны стимулировать воспаление, а также регулировать апоптоз и некроз клеток печени, индуцировать фиброз. Цитокины осуществляют свои функции в организме через взаимодействие с мембранно-связанными и растворимыми рецепторами на поверхности клеток, причем растворимые формы рецепторов могут действовать как антагонисты, так и как усилители их биологических эффектов. Различия в уровне цитокинов, а также растворимых и мембранно-связанных цитокиновых рецепторов могут определяться наличием мутаций в разных областях соответствующих генов. Это может оказывать влияние на формирование сигнального пути, определяющего судьбу клеток (т.е. выживание, апоптоз или некроз) и соответственно, на развитие и прогрессирование НАЖБП, некоторые формы которой, в частности, стеатогепатит и цирроз, сопровождаются повышением программируемой смерти клеток печени. Однако, вопрос о том, влияет ли полиморфизм генов TNF и IL6, а также рецепторов TNF и IL6, на развитие и прогрессирование НАЖБП, в настоящее время изучен очень слабо. В статье представлены имеющиеся современные данные литературы о связи полиморфизма генов TNF, IL6, TNFRSF1A, TNFRSF1B, IL6R с развитием неалкогольной жировой болезни печени.

Ключевые слова

неалкогольная жировая болезнь печени; воспаление; цитокины; фактор некроза опухоли альфа; интерлейкин 6; рецепторы цитокинов; полиморфизм генов

Полный текст:

PDF

Литература

Висмонт Ф. И. Воспаление (патофизиологические аспекты): Уч. метод. пособиe. Мн.: БГМУ, 2006. 48 с.

Герасимова О. Н., Сигалович Е. У., Данковцева Е. Н., Наконечников С. Н., Никитин А. Г., Иванова З. В., Масенко В. П., Носиков В. В., Затейщиков Д. А. Связь носительства аллеля A полиморфного маркера G(-238)A гена TNF-α с неблагоприятным прогнозом у больных с хронической систолической сердечной недостаточностью // Кардиология. 2015. Т. 55, № 9. С. 25–30.

Курбатова И. В., Дуданова О. П., Топчиева Л. В. Роль полиморфизма rs4537545 (C>T) гена IL6R в развитии неалкогольного стеатогепатита // Медицинский академический журнал. 2016а. Т. 16, № 3. С. 144–147.

Курбатова И. В., Топчиева Л. В., Дуданова О. П. Экспрессия генов каспаз 3, 6, 8 и 9 в лейкоцитах периферической крови и концентрация IL-6 и TNF-a в плазме крови у носителей разных генотипов по полиморфному маркеру -174G>C гена IL6, ассоциированному с риском развития неалкогольного стеатогепатита // Бюллетень экспериментальной биологии и медицины. 2016б. Т. 162, № 9. C. 356–361.

Abiru S., Migita K., Maeda Y. et al. Serum cytokine and soluble cytokine receptor levels inpatients with non-alcoholic steatohepatitis // Liver Int. 2006. Vol. 26. P. 39–45. doi: 10.1111/j.1478–3231.2005.01191.x

Alexander-Miller M. A., Derby M. A., Sarin A. et al. Supraoptimal peptide-major histocompatibility complex causes a decrease in Bcl-2 levels and allows tumor necrosis factor alpha receptor II-mediated apoptosis of cytotoxic T lymphocytes // J. Exp. Med. 1998. Vol. 188. P. 1391–1399.

Aller R., de Luis D. A., Izaola O. et al. G308A polymorphism

of TNF-alpha gene is associated with insulin resistance and histological changes in non alcoholic fatty liver disease // Ann. Hepatol. 2011. Vol. 9. P. 439–444.

Atreya R., Mudter J., Finotto S. et al. Blockade of interleukin

trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo // Nat. Med. 2000. Vol. 6. P. 583–588.

Bank S., Skytt Andersen P., Burisch J. et al. Polymorphisms

in the Inflammatory Pathway Genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG Are Associated with Susceptibility of Inflammatory Bowel Disease in a Danish Cohort // PLoS ONE. 2014. Vol. 9. e98815. doi: 10.1371/journal.pone.0098815

Becker C., Fantini M. C., Schramm C. et al. TGFbeta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling // Immunity. 2004. Vol. 21. P. 491–501.

Bernstein L. E., Berry J., Kim S. et al. Effects of etanercept in patients with the metabolic syndrome // Arch. Intern. Med. 2006. Vol. 166. P. 902–908.

Bodmer J.‑L., Schneider P., Tschopp J. The molecular architecture of the TNF superfamily // Trends Biochem. Sci. 2002. Vol. 27. P. 19–26.

Braunersreuther V., Viviani G. L., Mach F., Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease // World Journal of Gastroenterology. 2012. Vol. 18. P. 727–735.

Brito H. O., Barbosa F. L., dos Reis R. C. et al. Evidence of substance P autocrine circuitry that involves TNF-α, IL-6, and PGE2 in endogenous pyrogen-iduced fever // J. Neuroimmun. 2016. Vol. 293. P. 1–7.

Bruun J. M., Verdich C., Toubro S. et al. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men // Eur. J. Endocrinol. 2003. Vol. 148. P. 535–542.

Cabal-Hierro L., Lazo P. S. Signal transduction by tumor necrosis factor receptors // Cellular Signalling. 2012. Vol. 24. P. 1297–1305. doi: 10.1016/j.cellsig.2012.02.006

Carulli L., Canedi I., Rondinella S. et al. Genetic polymorphisms in non-alcoholicfatty liver disease: interleukin-6 -174G/C polymorphismis associated with nonalcoholic steatohepatitis // Dig. LiverDis. 2009. Vol. 41 P. 823–828. doi: 10.1016/j.dld.2009.03.005

Cengiz M., Yasar D. G., Ergun M. A. et al. The role of interleukin-6 and interleukin-8 gene polymorphisms in non-alcoholic steatohepatitis // Hepat. Mon. 2014. Vol. 14, no. 12: e24635. doi: 10.5812/hepatmon.24635

Chen D., Liu J. L., Liu Y. et al. Lack of an association between -308G>A polymorphism of the TNF-α gene and liver cirrhosis risk based on a meta-analysis // Genet. Mol. Res. 2011. Vol. 10. P. 2765–2774. doi: 10.4238/2011.November.8.2

Chen W., Xu H., Wang X. et al. The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune

disease // International Immunopharmacology. 2015. Vol. 28. P. 146–153.

Chowdhury S. D., Ramakrishna B., Eapen C. E. et al. Fibrosis in non-alcoholic fatty liver disease: correlation with tumor necrosis factor-alpha polymorphisms // Tropical Gastroenterology. 2013. Vol. 34, no. 1. P. 31–35.

Copaci I., Micu L., Voiculescu M. The role of cytokines in non-alcoholic steatohepatitis. A review // Journal of Gastrointestinal and Liver Diseases. 2006. Vol. 15, no. 4. P. 363–373.

Crespo J., Cayón A., Fernández-Gil P. et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients // Hepatology. 2001. Vol. 34. P. 1158–1163.

Cressman D. E., Greenbaum L. E., DeAngelis R. A. et al. Liver failure and defective hepatocyte regeneration in interleukin-6‑deficient mice // Science. 1996. Vol. 274. P. 1379–1383.

Cubillas R., Kintner K., Phillips F. et al. Tumor necrosis factor receptor 1 expression is upregulated in dendritic cells inpatients with chronic HCV who respond to therapy // Hepat. Res. Treat. 2010: 429243. doi: 10.1155/2010/429243

Czaja A. J. Hepatic inflammation and progressive liver fibrosis in chronic liver disease // World J. Gastroenterol. 2014. Vol. 20. P. 2515–2532. doi: 10.3748/wjg.v20. i10.2515

Dandona P., Weinstock R., Thusu K. et al. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss // J. Clin. Endocrinol. Metab. 1998. Vol. 83. P. 2907–2910.

DeBerge M. P., Ely K. H., Wright P. F. et al. Shedding of TNF receptor 2 by effector CD8+ T cells by ADAM17 is important for regulating TNF-αavailability during influenza infection // J. Leukoc. Biol. 2015. Vol. 98. P. 423–434. doi: 10.1189/jlb. 3A0914-432RR

Deng Y., Li M., Wang J. et al. Susceptibility to hepatocellular

carcinoma inthe Chinesepopulation – associations with interleukin-6 receptorpolymorphism // Tumor Biol. 2014. Vol. 35. P. 6383–6388. doi: 10.1007/s13277‑014‑1863‑7

Depuydt B., Van Loo G., Vandenabeele P., Declercq W. Induction of apoptosis by TNF receptor 2 in a Tcell hybridoma is FADD dependent and blocked by caspase-8 inhibitors // J. Cell Sci. 2005. Vol. 118. P. 497–504. doi: 10.1242/jcs.01640

Doganci A., Eigenbrod T., Krug N. et al. The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo // J. Clin. Invest. 2005. Vol. 115. P. 313–325.

El-Assal O., Hong F., Kim W. H. et al. IL-6‑deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver // Cell Mol. Immunol. 2004. Vol. 1. P. 205–211.

Fernández-Real J. M., Broch M., Vendrell J. et al. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects // J. Clin. Endocrinol. Metab. 2000. Vol. 85, no. 3. P. 1334–1339.

Ferreira R. C., Freitag D. F., Cutler A. J. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory disease // Plos Genetics. 2013. Vol. 9, no. 4. e1003444. doi: 10.1371/journal.pgen.1003444

Fishman D., Faulds G., Jeffery R. et al. The effect of novel polymorphisms in the interleukin 6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis // J. Clin. Invest. 1998. Vol. 102. P. 1369–1376.

Fitzpatrick E., Dew T. K., Quaglia A. et al. Analysis of adipokine concentrationsin paediatric non-alcoholic fatty liver disease // Pediatr. Obes. 2012. Vol. 7. P. 471–479. doi: 10.1111/j.2047-6310.2012.00082.x

Galicia J. C., Tai H., Komatsu Y. et al. Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced // Genes. Immun. 2004. Vol. 5. P. 513–516.

Gaur U., Aggarwal B. B. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily // Biocem. Pharmac. 2003. Vol. 66. P. 1403–1408.

Giannitrapani L., Soresi M., Giacalone A. et al. IL-6 –174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma // OMICS. 2011. Vol. 15. P. 183–186. doi: 10.1089/omi.2010.0093

Glossop J. R., Dawes P. T., Nixon N. B., Mattey D. L. Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis // Arthritis Research & Therapy. 2005. Vol. 7. P. 1227–1234. doi: 10.1186/ar1816

Grunhage F., Rezori B., Neef M. et al. Elevated soluble tumor necrosis factor receptor 75 concentrations identifypatients with liver cirrhosis at risk of death // Clin. Gastroenterol. Hepatol. 2008. Vol. 6. P. 1255–1262. doi: 10.1016/j.cgh.2008.06.018

Haukeland J. W., Damås J. K., Konopski Z. et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2 // J. Hepatol. 2006. Vol. 44. P. 1167–1174. doi: 10.1016/j.jhep.2006.02.011

Herbein G., Mahlknecht U., Batliwalla F. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4 // Nature. 1998. Vol. 395. P. 189–194.

Honda M., Yamamoto S., Cheng M. et al. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection // J. immunol. 1992. Vol. 148. P. 2175–2180.

Horiuchi S., Koyanagi Y., Zhou Y. et al. Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism // Eur. J. Immunol. 1994. Vol. 24. P. 1945–1948

Hotamisligil G. S., Arner P., Caro J. F. et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance // J. Clin. Invest. 1995. Vol. 95. P. 2409–2415.

Hu Z. W., Luo H. B., Xu Y. M. et al. Tumor necrosis factor-alpha gene promoter polymorphisms in Chinese patients with nonalcoholic fatty liver diseases // Acta Gastroenterol Belg. 2009. Vol. 72. P. 215–221.

Hui J. M., Hodge A., Farrell G. C. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? // Hepatology. 2004. Vol. 40. P. 46–54.

Hurst S. M., Wilkinson T. S., McLoughlin R. M. et al. IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation // Immunity. 2001. Vol. 14. P. 705–714.

IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies // Lancet. 2012. Vol. 379. P. 1205–1213. doi: 10.1016/S0140-6736(11)61931-4

Jones S. A., Horiuchi S., Topley N. et al. The soluble interleukin 6 receptor: mechanisms of production and implications in disease // FASEB J. 2001. Vol. 15. P. 43–58.

Karimi M., Goldie L. C., Cruickshank M. N. et al. A critical assessment of the factors affecting reporter gene assays for promoter SNP function: a reassessment of -308 TNF polymorphism function using a novel integrated reporter system // Eur. J. Hum. Genet. 2009. Vol. 17. P. 1454–1462. doi: 10.1038/ejhg.2009.80

Kidane D., Chae W. J., Czochor J. et al. Interplay between DNA repair and inflammation, and the link to cancer // Crit. Rev. Biochem. Mol. Biol. 2014. Vol. 49, no. 2. P. 116–139. doi: 10.3109/10409238.2013.875514

Kim E. Y., Teh H. S. TNF type 2 receptor (p75) lowers the threshold of T cell activation // J. Immunol. 2001. Vol. 167. P. 6812–6820.

Kim S., Moon S. M., Kim Y. S. et al. TNFR1 promoter -329G/T polymorphism results in allele-specific repression of TNFR1 expression // Biochem. Biophys. Res. Commun. 2008. Vol. 368. P. 395–401. doi: 10.1016/j.bbrc.2008.01.098

Kopp H. P., Kopp C. W., Festa A. et al. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients // Arterioscler. Thromb. Vasc. Biol. 2003. Vol. 23. P. 1042–1047.

Kotake S., Sato K., Kim K. J. et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation // J. Bone Miner. Res. 1996. Vol. 11. P. 88–95. doi: 10.1002/jbmr.5650110113

Kugelmas M., Hill D. B., Vivian B. et al. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E // Hepatology. 2003. Vol. 38. P. 413–419.

Leite N. C., Salles G. F., Cardoso C. R., Villela-Nogueira C. A. Serum biomarkers in type 2 diabetic patients with nonalcoholicsteatohepatitis and advanced fibrosis // Hepatol. Res. 2013. Vol. 43. P. 508–515. doi: 10.1111/j. 1872-034X. 2012.01106. x

Lemmers A., Gustot T., Durnez A. et al. An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease // Clin. Exp. Immunol. 2009. Vol. 156. P. 518–527. doi: 10.1111/j.1365-2249.2009.03916x

Lesmana C. R., Hasan I., Budihusodo U. et al. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis // J. Dig. Dis. 2009. Vol. 10. P. 201–206. doi: 10.1111/j.1751-2980.2009.00386.x

Lin S. Y., Wang Y. Y., Sheu W. H. Increased serum soluble tumor necrosisfactor receptor levels are associated with insulin resistance in liver cirrhosis // Metabolism. 2004. Vol. 53. P. 922–926.

Liu X., Invernizzi P., Lu Y. et al. Genome-wide metaanalyses

identify three loci associated with primary biliary cirrhosis // Nat. Genet. 2010. Vol. 42. P. 658–660.

Locksley R. M., Killeen N., Lenardo M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology // Cell. 2001. Vol. 104. P. 487–501.

Lourdusamy A., Newhouse S., Lunnon K. et al. Identification of cis-regulatory variation influencing protein abundance levels in human plasma // Hum. Mol. Genet. 2012. Vol. 21. P. 3719–3726. doi: 10.1093/hmg/dds186

Lust J. A., Donovan K. A., Kline M. P. et al. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor // Cytokine. 1992. Vol. 4. P. 96–100.

MacEwan D. J. TNF ligands and receptor – a matter of life and death // Br. J. Pharmacol. 2002. Vol. 135. P. 855–875. doi: 10.1038/sj.bjp.0704549

Machado M. V., Martins A., Almeida R. et al. Does the simultaneous tumor necrosis factor receptor2, tumor necrosis factor promoter gene polymorphism represent a higher risk for alcoholic liverdisease? // Eur. J. Gastroenterol. Hepatol. 2009. Vol. 21. P. 201–205. doi: 10.1097/MEG.0b013e32831016e0

Marinos G., Naoumov N. V., Rossol S. et al. Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection // Gastroenterol. 1995. Vol. 108. P. 1453–1463.

McFarland-Mancini M. M., Funk H. M., Paluch A. M. et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor // J. Immunol. 2010. Vol. 184. P. 7219–7228.

Mells G. F., Floyd J. A., Morley K. I. Genome-wide association study identifies 12 new susceptibility loci for primary billiary cirrhosis // Nat. Genet. 2011. Vol. 43. P. 329–332. doi: 10.1038/ng.789

Melzer D., Perry J. R., Hernandez D et al. A genomewide association study identifies protein quantitative trait loci (pQTLs) // PloS Genet. 2008. Vol. 4: e1000072. doi: 10.1371/journal.pgen.1000072

Milner K., Van der Poorten D., Xu A. et al. Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease // Hepatology. 2009. Vol. 49. Р. 1926–1934.

Mitsuyama K., Sata M., Rose-John S. Interleukin-6 trans-signaling in inflammatory bowel disease // Cytokine Growth Factor Rev. 2006. Vol. 17. P. 451–461.

Müllberg J., Oberthur W., Lottspeich F. et al. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site // J. Immunol. 1994. Vol. 152. P. 4958–4968.

Müllberg J., Schooltink H., Stoyan T. et al. The soluble interleukin-6 receptor is generated by shedding // Eur. J. Immunol. 1993. Vol. 23. P. 473–480.

Muller-Newen G., Kohne C., Keul R. et al. Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing // Eur. J. Biochem. 1996. Vol. 236. P. 837–842.

Naveau S., Abella A., Raynard B. et al. Tumornecrosis factor soluble receptor p55 and lipid peroxidation inpatients with acute alcoholic hepatitis // Am. J. Gastroenterol. 2001. Vol. 96. P. 3361–3367.

Neurath M. F., Finotto S. IL-6 signaling in autoimmunity, chronic inflammation-associated cancer // Cytokine and Growth Factor Reveiws. 2011. Vol. 22. P. 83–89. doi: 10.1016/j. cytogfr. 2011.02.003

Ofei F., Hurel S., Newkirk J. et al. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM // Diabetes. 1996. Vol. 45. P. 881–885.

Pavkov M. E., Nelson R. G., Knowler W. C. et al. Elevation of circulating TNF receptors 1 and 2 increases the risk of end-stage renal disease in American Indians with type 2 diabetes // Kidney Int. 2015. Vol. 87. P. 812–819. doi: 10.1038/ki.2014.330

Plomgaard P., Bouzakri K., Krogh-Madsen R. et al. Tumor necrosis factor-alphainduces skeletal muscle insulin resistance in healthy humansubjects via inhibition of Akt substrate 160 phosphorylation // Diabetes. 2005. Vol. 54. P. 2939–2945. doi: 10.2337/diabetes.54.10.2939

Pаr A., Pаr G. Liver fibrosis: patho-physiology, diagnosis and treatment // Orvosi Hetilap. 2005. Vol. 146, no. 1. P. 3–13.

Rafiq S., Frayling T. M., Murray A. et al. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects // Genes Immun. 2007. Vol. 8. P. 552–559.

Roth J., De Souza G. E. P. Fever induction pathways: evidence from responses to systemic or local cytokine formation // Braz. J. Med. Biol. Res. 2001. Vol. 34. P. 301–314.

Safranow K., Dziedziejko V., Rzeuski R. et al. Plasma concentrations of TNF-α and its soluble receptors sTNFR1 and TNFR2 in patients with coronary artery disease // Tissue Antigens. 2009. Vol. 74. P. 386–392. doi: 10.1111/j.1399-0039.2009.01332.x

Saito T., Ji G., Shinzawa H. et al. Genetic variations in humans associated with differencesin the course of hepatitis C // Biochem. Biophys. Res. Commun. 2004. Vol. 317. P. 335–341.

Scheller J., Chalaris A., Schmidt-Arras D., Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6 // Biochim Biophys Acta. 2011. Vol. 1813. P. 878–888. doi: 10.1016/j.bbamcr.2011.01.034

Schulz M., Dotzlaw H., Neeck G. Ankylosing spondylitis and rheumatoid arthritis: serum levels of TNF-α and Its soluble receptors during the course of therapy with etanercept and infliximab // Biomed. Res. Int. 2014: 675108. doi: 10.1155/2014/675108

Sennikov S. V., Vasilyev F. F., Lopatnikova J. A. et al. Polymorphisms in the tumor necrosis factor receptor genes affect the expression levels of membranebound type I and type II receptors // Mediators Inflamm. 2014: 745909. doi: 10.1155/2014/745909

Shin S. P., Kim N. K., Kim J. H. et al. Association between

hepatocellular carcinoma and tumor necrosis factor alpha polymorphisms in South Korea // World J. Gastroenterol. 2015. Vol. 21. P. 13064–13072. doi: 10.3748/wjg.v21.146.13064

Soresi M., Giannitrapani L., D’Antona F. et al. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma // World J. Gastroenterol. 2006. Vol. 12. P. 2563–2568.

Stephens O. W., Zhang Q., Qu P. et al. An intermediate-

risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification // Blood. 2012. Vol. 119. P. 503–512. doi: 10.1182/blood-2011‑07‑367052

Streetz K. L., Tacke F., Leifeld L. et al. Interleukin6/gp130‑dependent pathways are protective during

chronic liver diseases // Hepatology. 2003. Vol. 38. P. 218–229. doi: 10.1053/jhep.2003.50268

Sun R., Tian Z., Kulkarni S., Gao B. IL-6 prevents T cellmediated hepatitis via inhibition of NKT cells in CD4+ T cell and STAT3‑dependent manners // J. Immunol. 2004. Vol. 172. P. 5648–5655.

Tarrats N., Moles A., Morales A. et al. Critical role of tumor necrosis factor receptor 1, but not 2, in hepaticstellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis // Hepatology. 2011. Vol. 54. P. 319–327. doi: 10.1002/hep.24388

Taub R. Hepatoprotection via the IL-6/Stat3 pathway // J. Clin. Invest. 2003. Vol. 112. P. 978–980.

Tokushige K., Takakura M., Tsuchiya-Matsushita N. et al. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis // J. Hepatol. 2007. Vol. 46. P. 1104–1110. doi: 10.1016/j.jhep.2007.01.028

Trebicka J., Krag A., Gansweid S. et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt // Eur. J. Gastroenterol. Hepatol. 2011. Vol. 23. P. 1218–1225. doi: 10.1097/MEG.0b013e32834a75dc

Valenti L., Fracanzani A. L., Dongiovanni P. et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease // Gastroenterology. 2002. Vol. 122. P. 274–280.

van Dongen J., Jansen R., Smit D. et al. The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels // Behav. Genet. 2014. Vol. 44. P. 368–382. doi: 10.1007/s10519‑014‑9656‑8

Wang J., Ni H., Chen L. et al. Preparation and analysis of cSNP chip on hepatocellular carcinoma-related genes // Hepatobiliary Pancreat. Dis. Int. 2005. Vol. 4. P. 398–402.

Wang J. K., Feng Z. W., Li Y. C. et al. Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: ameta-analysis // J. Gastroenterol Hepatol. 2012. Vol. 27. P. 670–676. doi: 10.1111/j.1440-1746.2011.06978.x

Weifeng Y., Li L., Yujie H. et al. Inhibition of acute lung injury by tnfr-fc through regulation of an inflammation-oxidative stress pathway // PLoS One. 2016. Vol. 11, no. 3: e0151672. doi: 10.1371/journal.pone.0151672

Wieckowska A., Papouchado B. G., Li Z. et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis // Am. J. Gastroenterol. 2008. Vol. 103. P. 1372–1379. doi:10.1111/j.1572-0241.2007.01774.x

Yoneda M., Mawatari H., Fujita K. et al. High-sensitivity C-reactive protein is anindependent clinical feature of nonalcoholic steatohepatitis (NASH) and alsoof the severity of fibrosis in NASH // J. Gastroenterol. 2007. Vol. 42. P. 573–582. doi: 10.1007/s00535‑007‑2060‑x

Zekri A. R., Haleem H. A., Esmat G. E. et al. Immunomodulators, sFas and Fas-L as potential noninvasive

predictors of IFN treatment in patients with HCV genotype-

// J. Viral. Hepatol. 2007. Vol. 14. P. 468–477.

Zhou Y.‑J., Li Y.‑Y., Nie Y.‑Q. et al. Influence of polygenetic

polymorphisms on the susceptibility to non-alcoholic fatty liver disease of Chinese people // J. Gastroenterol. Hepatol. 2010. Vol. 25. P. 772–777. doi:10.1111/j.1440-1746.2009.06144x

Reference in English

Gerasimova O. N., Sigalovich E. U., Dankovtseva

E. N. Nakonechnikov S. N., Nikitin A. G., Ivanova Z. V.,

Masenko V. P., Nosikov V. V., Zateishchikov D. A.

Svyaz’ nositel’stva allelya A polimorfnogo markera

G(-238)A gena TNF-α s neblagopriyatnym prognozom

u bol’nykh s khronicheskoi sistolicheskoi serdechnoi

nedostatochnost’yu [Carriage of A allele of polymorphic

marker G(-238)A of TNF-α gene is associated with unfavorable

prognosis in patients with chronic systolic heart

failure]. Kardiologiya [Cardiology]. 2015. Vol. 55, no. 9.

P. 25–30.

Kurbatova I. V., Dudanova O. P., Topchieva L. V. Rol’ polimorfizma rs4537545 (C>T) gena IL6R v razvitii nealkogol’nogo steatogepatita [Role of rs4537545 (C>T) polymorphism of IL6R gene in the development of the nonalcoholic steatohepatitis]. Meditsinskii akademicheskii zhurnal [Medical Acad. Journal]. 2016a. Vol. 16, no. 3. P. 144–147.

Kurbatova I. V., Topchieva L. V., Dudanova O. P. Ekspressiya genov kaspaz 3, 6, 8 i 9 v leikotsitakh perifericheskoi krovi i kontsentratsiya IL-6 i TNF-a v plazme krovi u nositelei raznykh genotipov po polimorfnomu markeru -174G>C gena IL6, assotsiirovannomu s riskom razvitiya nealkogol’nogo steatogepatita [Expression rates of the 3, 6, 8 and 9 caspase genes in peripheral blood leukocytes and the concentration of IL-6 and TNF-a in blood plasma of donors with different genotypes for the -174G>C polymorphous marker of IL6 gene

associated with the risk of nonalcoholic steatohepatitis development]. Byulleten’ eksperimental’noi biologii i meditsiny [Bull. of Experimental Biology and Medicine]. 2016b. Vol. 162, no. 9. P. 356–361.

Vismont F. I. Vospalenie (patofiziologicheskie aspekty). Uch.‑metod. posobie [Inflammation (pathophysiological aspects)]. Minsk: BGMU, 2006. 48 p.