CYTOKINES AND CHEMOKINES IN THE BLOOD PLASMA OF PATIENTS WITH CHRONIC HEPATITIS C

Cover Page

Cite item

Abstract

Abstract. Pathogenesis of chronic hepatitis C (CHC) remains to be determined. Mechanisms of liver parenchyma damage in patients with CHC are complex and different. Cytokines play the role of intermediaries in the process of fibrosis development and chronic inflammation. In the present study levels of 27 cytokines in the blood plasma of 14 patients with CHC were tested using multiplex analysis. The liver biopsy was performed in all patients to define the activity of inflammation (histological activity index) and the degree of fibrosis. Nineteen samples of blood plasma obtained from healthy individuals were served as a control group in this study. The following cytokines were measured: IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, FGF-2, G-CSF, GM-CSF, IFNγ, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, PDGF-BB, TNFα and VEGF. In patients with CHC elevated levels of plasma IL-1ra, IL-6, IL-7, IFNγ, IL-12 (p70), IL-4, IL-9, IL-8, IP-10, eotaxin, MCP-1, MIP-1β, TNFα, G-CSF and GM-CSF were found in compare with the control group. At the same time levels of FGF-2 and PDGF-BB were reduced in patients with CHC in compare with controls. Differences in the production of IL-1ra, IL-6, IL-7, IFNγ, IL-12 (p70), IL-4, IL-9, IL-8, IP-10, eotaxin, MCP-1, MIP-1β, TNFα, G-CSF and GM-CSF were depend on the genotype of HCV (3a or 1b), histological activity index in liver tissue and the degree of liver fibrosis. The revealed changes of cytokine production in patients with CHC characterize different orientation of regulatory violations confirming that CHC is an immunopathological process.

About the authors

K. A. Sysoev

Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Санкт-Петербург

Author for correspondence.
Email: ksyssoev@mail.ru

к.м.н., старший научный сотрудник НМЦ по молекулярной медицине МЗ РФ

197022, Санкт-Петербург, ул. Льва Толстого, 6/8

Russian Federation

A. V. Chukhlovin

Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова, Санкт-Петербург

Email: ksyssoev@mail.ru
Russian Federation

D. M. Shakhmanov

Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург

Email: ksyssoev@mail.ru
Russian Federation

K. V. Zhdanov

Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург

Email: ksyssoev@mail.ru
Russian Federation

Areg A. Totolian

ФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург

Email: ksyssoev@mail.ru
Russian Federation

References

  1. Жданов К.В., Гусев Д.А., Чирский В.С., Сысоев К.А., Якубовская Л.А., Шахманов Д.М., Тотолян Арег А. Экспрессия хемокинов и их рецепторов в крови и ткани печени при хроническом вирусном гепатите С // Медицинская иммунология. — 2007. — Т. 9, № 4–5. — С. 379–388.
  2. Antonelli A., Ferri C., Ferrari S.M., Ghiri E., Goglia F., Pampana A., Bruschi F., Fallahi P. Serum levels of proinflammatory cytokines interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia // Arthritis Rheum. — 2009. — Vol. 60. — P. 3841–3847.
  3. Apolinario A., Diago M., Lo Iacono O., Lorente R., Pérez C., Majano P.L., Clemente G., García-Monzón C. Increased circulating and intrahepatic T-cell-specific hemokines in chronic hepatitis C: relationship with the type of virological response to peginterferon plus ribavirin combination therapy // Aliment. Pharmacol. Ther. — 2004. — Vol. 19. — P. 551–562.
  4. Bedossa P., Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group // Hepatology. — 1996. — Vol. 24. — P. 289–293.
  5. Bonte D., Francois C., Castelain S., Wychowski C., Dubuisson J., Meurs E.F., Duverlie G. Positive effect of the hepatitis C virus nonstructural 5A protein on viral multiplication // Arch. Virol. — 2004. — Vol. 149. — P. 1353–1371.
  6. Charles E.D., Dustin L.B. Hepatitis C virus-induced cryoglobulinemia // Kidney Int. — 2009. — Vol. 76. — P. 818–824.
  7. Ciesek S., Liermann H., Hadem J., Greten T., Tillmann H.L., Cornberg M., Aslan N., Manns M.P., Wedemeyer H. Impaired TRAIL-dependent cytotoxicity of CD1c-positive dendritic cells in chronic hepatitis C virus infection // J. Viral. Hepat. — 2008. — Vol. 15. — P. 200–211.
  8. Cook P.C., Jones L.H., Jenkins S.J., Wynn T.A., Allen J.E., MacDonald A.S. Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo // Proc. Nat. Acad. Sci. USA. — 2012. — Vol. 109. — P. 9977–9982.
  9. Della Bella S., Crosignani A., Riva A., Presicce P., Benetti A., Longhi R., Podda M., Villa M.L. Decrease and dysfunction of dendritic cells correlate with impaired hepatitis C virus-specific CD4+ T-cell proliferation in patients with hepatitis C virus infection // Immunology. — 2007. — Vol. 121. — P. 283–292.
  10. Dental C., Florentin J., Aouar B., Gondois-Rey F., Durantel D., Baumert T.F., Nunes J.A., Olive D., Hirsch I., Stranska R. Hepatitis C virus fails to activate NF-κB signaling in plasmacytoid dendritic cells // J. Virol. — 2012. — Vol. 86. — P. 1090–1096.
  11. Douglas M.W., George J. Molecular mechanisms of insulin resistance in chronic hepatitis C // World J. Gastroenterol. — 2009. — Vol. 15. — P. 4356–4364.
  12. Fujiyoshi M., Ozaki M. Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseases // J. Hepatobiliary Pancreat. Sci. — 2011. — Vol. 18. — P. 13–22.
  13. Golden-Mason L., Burton J.R. Jr., Castelblanco N., Klarquist J., Benlloch S., Wang C., Rosen H.R. Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence // Hepatology. — 2006. — Vol. 44. — P. 1098–1109.
  14. Goswami R., Kaplan M.H. A brief history of IL-9 // J. Immunol. — 2011. — Vol. 186. — P. 3283–3288.
  15. Green J., Khabar K.S., Koo B.C., Williams B.R., Polyak S.J. Stability of CXCL-8 and related AU-Rich mRNAs in the context of hepatitis C virus replication in vitro // J. Infect. Dis. — 2006. — Vol. 193. — P. 802–811.
  16. Hirano T., Taga T., Nakano N., Yasukawa K., Kashiwamura S., Shimizu K., Nakajima K., Pyun K.H., Kishimoto T. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2) // Proc. Natl. Acad. Sci. USA. — 1985. — Vol. 82. — P. 5490–5494.
  17. Knodell R.G., Ishak K.G., Black W.C., Chen T.S., Craig R., Kaplowitz N., Kiernan T.W., Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis // Hepatology — 1981. — Vol. 1. — P. 431–435.
  18. Larrubia J.R., Calvino M., Benito S., Sanz-de-Villalobos E., Perna C., Pérez-Hornedo J., González-Mateos F., García-Garzón S., Bienvenido A., Parra T. The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection // J. Hepatol. — 2007. — Vol. 47. — P. 632–641.
  19. Leroy V., Vigan I., Mosnier J.F., Dufeu-Duchesne T., Pernollet M., Zarski J.P., Marche P.N., Jouvin-Marche E. Phenotypic and functional characterization of intrahepatic T lymphocytes during chronic hepatitis C // Hepatology. — 2003. — Vol. 38. — P. 829–841.
  20. Libra M., Mangano K., Anzaldi M., Quattrocchi C., Donia M., di Marco R., Signorelli S., Scalia G., Zignego A.L., de Re V., Mazzarino M.C., Nicoletti F. Analysis of interleukin (IL)-1β IL-1 receptor antagonist, solu ble IL-1 receptor type II and IL-1 accessory protein in HCV-associated lymphoproliferative disorders // Oncol. Rep. — 2006. — Vol. 15. — P. 1305–1308.
  21. Marra F., Romanelli R.G., Giannini C., Failli P., Pastacaldi S., Arrighi M.C., Pinzani M., Laffi G., Montalto P., Gentilini P. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells // Hepatology. — 1999. — Vol. 29. — P. 140–148.
  22. Mengshol J. A., Golden-Mason L., Castelblanco N., Im K.A., Dillon S.M., Wilson C.C., Rosen H.R.; Virahep-C Study Group. Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes // Gut. — 2009. — Vol. 58. — P. 964 –973.
  23. Mukaida N. Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation // Int. J. Hematol. — 2000. — Vol. 72. — P. 391–398.
  24. Nowak E.C., Noelle R.J. Interleukin-9 as a T helper type 17 cytokine // Immunology. — 2010. — Vol. 131. — P. 169 –173.
  25. Patzwahl R., Meier V., Ramadori G., Mihm S. Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization // J. Virol. — 2001. — Vol. 75. — P. 1332–1338.
  26. Rodrigue-Gervais I.G., Rigsby H., Jouan L., Sauvé D., Sékaly R.P., Willems B., Lamarre D. Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection // J. Immunol. — 2010. — Vol. 184. — P. 3134 –3144.
  27. Schwabe R.F., Brenner D.A. Mechanisms of liver injury. I. TNFalpha-induced liver injury: role of IKK, JNK, and ROS pathways // Am. J. Physiol. Gastrointest. Liver Physiol. — 2006. — Vol. 290. — P. G583–G589.
  28. Shields P.L., Morland C.M., Salmon M., Qin S., Hubscher S.G., Adams D.H. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver // J. Immunol. — 1999. — Vol. 163. — P. 6236–6243.
  29. Sprengers D., van der Molen R.G., Kusters J.G., Kwekkeboom J., van der Laan L.J., Niesters H.G., Kuipers E.J., De Man R.A., Schalm S.W., Janssen H.L. Flow cytometry of fineneedle-aspiration biopsies: a new method to monitor the intrahepatic immunological environment in chronic viral hepatitis // J. Viral. Hepat. — 2005. — Vol. 12. — P. 507–512.
  30. Sugimoto R., Enjoji M., Nakamuta M., Ohta S., Kohjima M., Fukushima M., Kuniyoshi M., Arimura E., Morizono S., Kotoh K., Nawata H. Effect of IL-4 and IL-13 on collagen production in cultured LI90 human hepatic stellate cells // Liver Int. — 2005. — Vol. 25. — P. 420–428.
  31. Tacke F., Trautwein C., Yagmur E., Hellerbrand C., Wiest R., Brenner D.A., Schnabl B. Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course // J. Gastroenterol. Hepatol. — 2007. — Vol. 22. — P. 1256–1264.
  32. Takaki A., Tatsukawa M., Iwasaki Y., Koike K., Noguchi Y., Shiraha H., Sakaguchi K., Nakayama E., Yamamoto K. Hepatitis C virus NS4 protein impairs the Th1 polarization of immature dendritic cells // J. Viral. Hepat. — 2010. — Vol. 17. — P. 555–562.
  33. Tarrats N., Moles A., Morales A., García-Ruiz C., Fernández-Checa J.C., Marí M. Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis // Hepatology. — 2011. — Vol. 54. — P. 319 –327.
  34. Tawadrous G.A., Aziz A.A., Amin D.G., Eldemery A., Mostafa M.A. RANTES, TNFα, oxidative stress, and hematological abnormalities in hepatitis C virus infection // J. Investig. Med. — 2012. — Vol. 60. — P. 878–882.
  35. Vargas A., Berenguer J., Catalan P., Miralles P., López J.C., Cosín J., Resino S. Association between plasma levels of eotaxin (CCL-11) and treatment response to interferon-alpha and ribavirin in HIV/HCV co-infected patients // J. Antimicrob. Chemother. — 2010. — Vol. 65. — P. 303–306.
  36. Watowich S.S., Liu Y.J. Mechanisms regulating dendritic cell specification and development // Immunol. Rev. — 2010. — Vol. 238. — P. 76–92.
  37. Weng H.L., Liu Y., Chen J.L., Huang T., Xu L.J., Godoy P., Hu J.H., Zhou C., Stickel F., Marx A., Bohle R.M., Zimmer V., Lammert F., Mueller S., Gigou M., Samuel D., Mertens P.R., Singer M.V., Seitz H.K., Dooley S. The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis // Hepatology. — 2009. — Vol. 50. — P. 230–243.
  38. Wu J., Meng Z., Jiang M., Zhang E., Trippler M., Broe ring R., Bucchi A., Krux F., Dittmer U., Yang D., Roggendorf M., Gerken G., Lu M., Schlaak J.F. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific // Immunology — 2010. — Vol. 129. — P. 363–374.
  39. Ying Zh., Ma C.J., Ni L., Zhang C.L., Wu X.Y., Kumaraguru U., Li C.F., Moorman J.P., Yao Z.Q. Cross-talk between programmed death-1 and suppressor of cytokine signaling-1 in inhibition of IL-12 production by monocytes/macrophages in hepatitis C virus infection // J. Immunol. — 2011. — Vol. 186. — P. 3093–3103.
  40. Yoshimura T., Yuhki N., Moore S.K., Appella E., Lerman M.I., Leonard E.J. Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE // FEBS Lett. — 1989. — Vol. 244. — P. 487–493.
  41. Zhang L.J., Zheng W.D., Chen Y.X., Huang Y.H., Chen Z.X., Zhang S.J., Shi M.N., Wang X.Z. Antifibrotic effects of interleukin-10 on experimental hepatic fibrosis // Hepatogastroenterology. — 2007. — Vol. 54. — P. 2092–2098.

Copyright (c) 2014 Sysoev K.A., Chukhlovin A.V., Shakhmanov D.M., Zhdanov K.V., Totolian A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies