Preview

Medical Immunology (Russia)

Advanced search

ACTIVATION OF GENES CONTROLLING THE IMMUNE SIGNALING PATHWAYS: DIFFERENTIAL INDIVIDUAL SENSITIVITY OF HUMAN BLOOD CELLS FOR INTERFERON PREPARATIONS AND IFN INDUCERS

https://doi.org/10.15789/1563-0625-2015-1-7-18

Abstract

We have studied dose effects of several Interferon (IFN) inducers, i.e., Genfaxon (beta-1 IFN), Cycloferon and Immunomax upon expression of six genes controlling the signaling in immune pathways (TLR3, TLR4, RIG1, IRF3, IPS, B2M), by means of real-time RT-PCR, being tested with blood cells from three humans. It is revealed that individual cell samples showed different sensitivity to these drugs, probably, due to constitutive levels of TLR3 and TLR4 gene expression and possible connections with their immune pathology. Genfaxon at a dose of 104 ME produced potent stimulation of TLR3, TLR4, IRF3 and B2M genes in two persons. Immunomax, at a dose 0,5 unit, exhibited same effect in one case only (with Epstein-Barr virus infection). Cycloferon stimulated gene expression at much lower levels than Genfaxon in any cases. We have shown a reverse correlation between sensitivity of the cells to Immunomax, and constitutive TLR3 and TLR4 expression. The stimulatory effects of Immunomax were maximal in a person with very low TLR3/4 gene expression. Immunomax boosted the genes from several signaling pathways, including TLR3, TLR4, but genes of RIG/IPS pathway showed higher activation. Cycloferon induced gene transcription of IRF3 and B2M-receptor to higher degree, than expression of TLR3 and TLR4 genes. Hence, our data concerning Genfaxon, Immunomax and Cycloferon confirm their IFN-inducing effects upon human blood cells. The RT-PCR-based evaluation of gene expression related to signaling immune pathways in blood cell populations will enable rapid and highly specific quantitation of IFN and IFN-inducer drugs activities, thus avoiding their biological testing in long-term cell cultures. 

About the Authors

T. M. Sokolova
Federal State Budgetary Institution "N.F. Gamaleya Federal Reseach Centre for Epidemiology and Microbiology", Russian Ministry of Health Care 123098, Russian Federation, Moscow, Gamaleya str., 18. Phone: 7 (499) 193-43-19. Fax: 7 (499) 193-61-83.
Russian Federation

PhD, MD (Biology), Leading Research Associate, Laboratory of Interferongenesis, FSBI "N.F. GamaleyaFederalReseachCentreforEpidemiologyand Microbiology", Russian Ministry of Health Care, Moscow, Russian Federation 



A. N. Shuvalov
Federal State Budgetary Institution "N.F. Gamaleya Federal Reseach Centre for Epidemiology and Microbiology", Russian Ministry of Health Care 123098, Russian Federation, Moscow, Gamaleya str., 18. Phone: 7 (499) 193-43-19. Fax: 7 (499) 193-61-83.
Russian Federation

PhD Fellow, Junior Research Associate, Laboratory of Interferongenesis, FSBI "N.F. Gamaleya Federal ReseachCentreforEpidemiologyandMicrobiology",Russian Ministry of Health Care, Moscow, Russian Federation 



I. M. Shapoval
Federal State Budgetary Institution "N.F. Gamaleya Federal Reseach Centre for Epidemiology and Microbiology", Russian Ministry of Health Care 123098, Russian Federation, Moscow, Gamaleya str., 18. Phone: 7 (499) 193-43-19. Fax: 7 (499) 193-61-83.
Russian Federation

PhD (Biology), Senior Research Associate, Department of Interferongenesis, FSBI "N.F. Gamaleya FederalReseachCentreforEpidemiologyandMicrobiology", Russian Ministry of Health Care, Moscow, Russian Federation 



Z. A. Sokolova
FSBSI "N.N. Blokhin Russian Cancer Research Center", Moscow, Russian Federation
Russian Federation

PhD (Medicine), Senior Research Associate, FSBSI "N.N. Blokhin Russian Cancer Research Center", Moscow, Russian Federation 



F. I. Ershov
Federal State Budgetary Institution "N.F. Gamaleya Federal Reseach Centre for Epidemiology and Microbiology", Russian Ministry of Health Care 123098, Russian Federation, Moscow, Gamaleya str., 18. Phone: 7 (499) 193-43-19. Fax: 7 (499) 193-61-83.
Russian Federation

PhD, MD (Medicine), Professor, Full Member of Russian Academy of Sciences, Chief, Department of Interferons and Laboratory of Interferongenesis, FSBI "N.F. Gamaleya Federal Reseach Centre for Epidemiology and Microbiology", Russian Ministry of Health Care, Moscow, Russian Federation 



References

1. Атауллаханов Р.И., Пичугин А.В., Шишкова Н.М., Мастернак Т.Б., Малкина Е.Ю., Ульянова Л.И., Стеценко О. Н. Клеточные механизмы иммуномодулирующего действия препарата Иммуномакса // Иммунология, 2005. Т.26, No 2. С. 111-120. [Ataullakhanov R.I., Pichugin A.V., Shishkova N.M., Masternak Т.В., Malkina E.Yu., Ulyanova L.I., Stetsenko O.N. Cell mechanisms of the immunomodulating action produced by drug «Immunomax». Immunologiya = Immunology, 2005, Vol. 26, no. 2, pp. 111-120. (In Russ.)]

2. Ершов Ф.И. Антивирусные препараты. Справочник (2-е изд.). М.: ГЭОТАР-Медиа, 2006, 312 с. [Ershov F.I. Antiviral preparations]. Moscow: GEOTAR-Media, 2006, 312 p.

3. Деева Е.Г., Павловская Я.В., Киселев О.И., Киселев В.И., Пиотровский Л.Б., Ершов Ф.И. Структурный и функциональный анализ биологически активных производных акридина // Вестник Российской Академии наук, 2004. No 2. С. 29-34. [Deeva E.G., Pavlovskaia Ia.V., Kiselev O.I., Kiselev V.I., Piotrovskii L.B., Ershov F.I. The structural and functional analysis of the biological activity of acridine derivates. Vestnik Rossiyskoy Akademii nauk = Bulletin of the Russian Academy of Medical Sciences, 2004, no. 2, pp. 29-34. (In Russ.)]

4. Коваленко А.Л., Казаков В.И., Слита А.В., Зарубаев В.В., Сухинин В.П. Исследование внутриклеточной локализации циклоферона, связывание его с ДНК и стимуляции экспрессии цитокинов в клетках при воздействии циклоферона // Цитология, 2000. Т. 42, No 7. С.659-664. [Kovalenko A. L., Kazakov V.I., Slita A.V., Zarubaev V.V., Sukhinin V.P. Intracellular localization of cycloferon, its binding with DNA and stimulation of cytokines expression after exposure to cycloferon. Tsitologiya = Cytology, 2000, Vol. 42, no. 7, pp. 659-664. (In Russ.)]

5. Лацерус Л.А., Пинигина И.М., Барышников А.Ю., Огородникова М.В. Цитотоксические и апоптозиндуцирующие активности препарата Абисилин в отношении опухолевых клеток // Российский биотерапевтический журнал, 2010. No 1. С. 9-12. [Latseruz L.A., Pinigina N.M., Baryshnikov A.Yu., Ogorodnikova M.V. The cytotoxic apoptosis-inducing activity of Ambisilin. Rossiyskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapeutic, 2010, no. 1, pp. 9-12. (In Russ.)]

6. Новиков А.Г., Логунова З.В., Потекаев Н.Н. Опыт применения иммуномодулятора «Иммуномакс» // Российский медицинский журнал, 2004, Т. 12, No 13. С. 819-820. [Novikov А.G., Logunovа Z.V., Potekaev N.N. Experience of using immunomodulator «Immunomax». Rossiyskiy meditsinskiy zhurnal = Russian Medical Journal, 2004, Vol. 12, no. 13, pp. 819-820. (In Russ.)]

7. Романцов М.Г., Ершов Ф.И., Коваленко А.Л. Циклоферон в лечении инфекционных заболеваний // Антибиотики и химиотерапия, 2008. Т. 53, No 3-4. С. 36-45. [Romantsov M.G., Ershov F.I., Kovalenko A.L. Cycloferon in the treatment of infectious diseases. Antibiotiki i khimioterapiya = Antibiotic and Chemotherapy, 2008, Vol. 53, no. 3-4, pp. 36-45. (In Russ.)]

8. Соколова Т.М. Иммунное узнавание вирусных нуклеиновых кислот приводит к индукции интерферонов и воспалительных цитокинов. Сборник научных трудов «Интерферон-2011» / Под ред. Ершова Ф.И. М.: НИИЭМ им. Н.Ф. Гамалеи МЗ РФ, 2012. С. 52-62. [Sokolova Т. М. Immune recognition viral nucleic acids result in interferon and inflammatory cytokines induction. “Interferon-2011”]. Moscow: NF Gamaleya Institute of Microbiology, Epidemiology and Immunology, 2012, pp. 52-62.

9. Соколова Т.М., Урываев Л.В., Тазулахова Э.Б., Ершов Ф.И., Малышенкова И.К., Дидковский Н.А. Индивидуальные изменения экспрессии генов системы интерферона в клетках крови человека под влиянием амиксина и циклоферона // Вопросы вирусологии, 2005. No 2. С.32-36. [Sokolova T.M., Uryvaev L.V., Tazulakhova E.В., Ershov F.I., Malyshenkova I.K., Didkovsky N.A. Individual changes of gene expression in the interferon system in human blood cells due to amixin and cycloferon. Voprosy Virusologii = Problems of Virology, 2005, no. 2, pp. 32-36. (In Russ.)]

10. Соколова Т.М., Федорова Н.Е., Меджидова М.Г., Терехов С.М., Урываев Л.В., Кущ А.А. Механизмы клеточной резистентности к цитомегаловирусу связаны с пролиферативным состоянием клеток и транскрипционной активностью генов лейкоцитарного и иммунного интерферона // Медицинская иммунология, 2007. Т. 9, No 4-5. С.457-466. [Sokolova T.M., Fedorova N.E., Medjidova M.G., Terekhov S.M., Uryvaev L.V., Kushch A.A. Mechanisms of cell resistance to cytomegalovirus are connected with cell proliferation state and transcription activity of leukocyte and immune interferon genes. Meditsinskaya immunologiya = Medical Immunology (Russia), 2007, Vol. 9, no. 4-5, pp. 457-466. (In Russ.)]

11. Соколова Т.М., Оспельникова Т.П., Колодяжная Л.В., Шувалов А.Н., Чкадуа Г.З., Ершов Ф.И. Эффекты индукторов интерферона на экспрессию генов – регуляторов апоптоза в лимфоцитах человека //Цитокины и воспаление, 2011. Т.10, No 2. С. 75-81. [Sokolova T.M., Ospelnikova T.P., Kolodyazhnaya L.V., Shuvalov A.N., Chkadua G.Z. Effects of interferon inducers on the expression of apoptosis regulatory genes in human lymphocytes. Tsitokiny i vospalenie = Cytokines and Inflammation, 2011, Vol. 10, no. 2, pp. 75-81. (In Russ.)]

12. Соколова Т.М., Шувалов А.Н. Телков М.В., Колодяжная Л.В., Ершов Ф.И. Препарат «Ридостин» индуцирует транскрипцию широкого спектра генов системы интерферона в клетках человека // Бюллетень экспериментальной биологии и медицины, 2013. Т. 156, No 8. С. 179-182. [Sokolova T.M., Shuvalov A.N., Telkov M.V., Kolodyazhnaya L.V., Ershov F.I. Preparation “Ridostin” induces transcription wide genes spectrum of interferon system in human cells. Byulleten` eksperimental`noy biologii i meditsiny = Bulletin of Experimental Biology and Medicine, 2013, Vol. 156, no. 8, pp. 179-182. (In Russ.)]

13. Суханов Д.С., Романцов М.Г., Смагина Ф.И., Коваленко А.Л., Локтева О.М. Доза зависимая интерферон индуцирующая активность и фармакинетика циклоферона у здоровых лиц // Экспериментальная и клиническая фармакология, 2012. No 75. С.23-26. [Sukhanov D.S., Romantsov M.G., Smagina A.N., Kovalenko A.L. Lokteva O.M. Dose-dependent interferon induction activity and pharmacokinetics of cycloferon in healthy humans. Eksperimental`naya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology, 2012, Vol. 75, no. 1, pp. 23-26. (In Russ.)]

14. Шувалов А.Н., Соколова Т.М., Шаповал И.М., Ершов Ф.И. Модуляция клеточных генов препаратом Иммуномакс: активация генов интерферонов и интерлейкинов // Иммунология, 2014. No 1. C. 17-21. [Shuvalov A.N., Sokolova T.M., Shapoval I.M., Ershov F.I. Modulation of cellular gene transcription by drug “Immunomax”: activation of Interferon and Interleukine genes. Immunologiya = Immunology, 2014, no. 1, pp. 17-21. (In Russ.)]

15. Ghochikyan A., Pichugin A., Bagaev A. Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist Immunomax, as a therapeutic strategy for a metastatic breast cancer. J. Transl. Med. 2014, Vol. 12, no. 1, pp. 322-333.

16. Black K.E., Collins S.L., Hagan R.S., Hambin M.J., Chan-Li Y., Hallowell R.W., Powell J.D., Horton M.R.. Hyaluronan fragments induce IFNβ via a novel TLR4-TRIF-TBK1-IRF3-dependent pathway. Journal of Inflammation, 2013, Vol. 10, pp. 23-32.

17. Calvar T., Deimling T., Ablasser A., Hopfner K-P., Hornung V. Species-specific detection of the antiviral small-molecule compound CMA by STING. The EMBO J., 2013, Vol. 32, pp.1440-1450.

18. Cholewiriski G., Dzierzbicka K., Kotodziejczyk A.M. Natural and synthetic acridines /acridones as antitumor agents: their biological activities and methods of synthesis. Parmacologicals Reports, 2011, Vol. 63, pp. 305-336.

19. Denkow K., Baur J.M.J., Herker M., Paap B.K., Thamilarassan M., Koszan D., Shott E., Deuschle K., BellmanStrobl J., Paul F., Zettl U.K., Ruprecht K., Lehnard S. Multiple Sclerosis: Modulation of Toll-Like receptors (TLR) expression by interferon -β includes upregulation of TLR7 in plasmacytoid dendritic cells. Plos one, 2013, Vol. 8, issue 8, e70626, pp. 1-11.

20. George P.M., Badiger R., Alazawi W., Foster G.R., Mitchell J.A. Pharmacology and therapeutic potential of interferons. Parmacology and Therapeutics, 2012, Vol. 135, pp. 44-53.

21. Gonzalez-Navajas J.M., Lee J., Daid M., Raz E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol., 2013, Vol. 12, no. 2, pp. 125-135.

22. Iwasaki A., Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science, 2010, Vol. 327, pp. 291-295.

23. Lester S.N., Li K. Toll-like receptors in antiviral innate immunity. J.Mol.Biol., http:// dx.dos.org/10.1016. jmb.2013.11.024.

24. Levy D.E., Marie I., Durbin J.E. Induction and Function of Type I and III Interferon in response to viral infection. Curr Opin Virol., 2011, Vol. 1, no. 6, pp. 476-486.

25. Miettinen M., Sareneva T., Julkunen I., Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes and Immunity, 2001, Vol. 2, pp. 349-355.

26. Paul-Clark M.J., George P.M., Cateral T., Parzych K., Wright W.R., Crawford D., Bailey L.K., Reed D.M., Mitchell J.A. Pharmacology and therapeutic potential of pattern recognition receptors. Pharmacology and Therapeutics, 2012, Vol. 135, pp. 200-215.

27. Platanias L.C. Mechanisms of type 1and type-IIinterferon-mediated signaling. Nat. Rev. immunol, 2005, Vol. 5, pp. 375-386.

28. Sadler A.J., Williams B.R. Interferon-inducible antiviral effectors. Nat. Rev. Immunol., 2008, Vol. 8, pp. 559–568.

29. Siren J., Pirhonen J., Julkunen I., Matikainen S. IFN-α regulates TLR-dependent gene expression of IFN-α, IFN-β, IL28 and IL29. J. Immunol., 2005, Vol. 174, pp. 1932-1937.

30. Vispe S., Vandenberghe I., Rubin M. Novel tetra-acridine derivates as dual inhibitors of topoisomerase II and the human proteasome. Biochem. Pharmacol., 2007, Vol. 73, no. 12, pp.1863-1872.

31. Wang W.G., Ho W.C., Dicker D.T., Mackinnon C.,Winkler J.D., Marmorstein R., El-Deiry W.C. Acridine derivates activate p53 and induce tumor cell death through Bax. Cancer Biol. Ther., 2005, Vol. 4, pp. 893-898.

32. Zarubaev V.V., Slita A.V., Krivitskaya V.Z., Sirotkin A.K., Kovalenko A.L., Chatterjii N.K. Direct antiviral effects of cycloferon (10-carboxymethyl-0-acridanone) against adenovirus type 6 in vitro. Antiviral Res., 2003, Vol. 58, no. 2, pp. 131-137.


Review

For citations:


Sokolova T.M., Shuvalov A.N., Shapoval I.M., Sokolova Z.A., Ershov F.I. ACTIVATION OF GENES CONTROLLING THE IMMUNE SIGNALING PATHWAYS: DIFFERENTIAL INDIVIDUAL SENSITIVITY OF HUMAN BLOOD CELLS FOR INTERFERON PREPARATIONS AND IFN INDUCERS. Medical Immunology (Russia). 2015;17(1):7-18. (In Russ.) https://doi.org/10.15789/1563-0625-2015-1-7-18

Views: 1557


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


ISSN 1563-0625 (Print)
ISSN 2313-741X (Online)