Journal of Literature Pharmacy Sciences

İmmün Sistemde Mikrorna'ların Rolü ve Terapötik Yaklaşımlar
Role of MicroRNAs in the Immune System and Therapeutic Approaches
Hatice Gül ANLARa, Nurşen BAŞARANb
aFarmakoloji Toksikoloji ABD, Zonguldak Bülent Ecevit Üniversitesi Eczacılık Fakültesi, Zonguldak, TÜRKİYE
bFarmakoloji Toksikoloji ABD, Hacettepe Üniversitesi Eczacılık Fakültesi, Ankara, TÜRKİYE
J Lit Pharm Sci. 2019;8(3):235-44
doi: 10.5336/pharmsci.2019-66083
Article Language: TR
Full Text
ÖZET
 MikroRNA'lar; küçük, kodlamayan RNA'lar olup, hedef mRNA'lara bağlanıp bozulmalarını indükleyerek veya translasyonlarını inhibe ederek gen ekspresyonunu düzenlemektedirler. Her bir mikroRNA'nın yüzlerce hedefi olabilmekte, bu nedenle mikroRNA'lar genlerin büyük bir kısmının ekspresyonunu etkilemektedir. Yaklaşık 20 yıl önce memeli hücrelerinde keşfedilmelerinden beri, insan sağlığında ve hastalıklarında mikroRNA'ların rolü araştırılmaktadır. Yakın zamanda yapılan çalışmalar, mikroRNA'ların kalıtsal ve adaptif immün sistem hücrelerinde benzersiz bir ekspresyon profili ile bu hücrelerin gelişmesi ve fonksiyonlarında çok önemli rolleri olduğunu göstermiştir. miR-146 (146a ve 146b) ve miR-155, kalıtsal ve adaptif immün sistemin kontrolündeki çoklu rolleri ve bazı tümörlerdeki düzenleyici ve onkogenik rolleri nedeni ile, bu konuda en fazla araştırılan mikroRNA'lardır. İmmün sistemin uygun yanıtının organizasyonundaki hayati rollerinin dışında, mikroRNA'lar ayrıca, hücre içi immün mediyatör olarak görev almaktadırlar. Bu şekilde viral RNA'yı tanıyıp, viral RNA'nın stabilitesini ve translasyonunu negatif yönde düzenleyebilmektedirler. Dahası, mikroRNA'ların anormal ekspresyonu, immün sistem ile ilgili kanser ve otoimmün hastalıklar gibi patolojik durumların ortaya çıkmasında da rol oynayabilmektedir. Bu mikroRNA'ların çoğu, birçok hastalıkta biyogösterge olarak veya terapötik seçenek olarak incelenmektedir. Birçok vakada, mikroRNA ekpresyon paneli kanserin klinik ve/veya patolojik parametreleri ile ilişkili bulunmuştur. Bu çalışmada, mikroRNA'ların immün sistemin gelişmesindeki fonksiyonları hakkında genel bir değerlendirme sunulması, ayrıca, mikroRNA'ların anormal ekspresyonlarının patolojik rolü ve mikroRNA temelli terapötik yaklaşımların da vurgulanması amaçlanmıştır.

Anahtar Kelimeler: mikroRNAlar; bağışıklık sistemi
ABSTRACT
 MicroRNAs are small noncoding RNAs that regulate gene expression by binding to target mRNAs and either promoting their decay or inhibiting their translation. Each microRNAs can have hundreds of targets; therefore, microRNAs influence the expression of a large proportion of genes. The functions of microRNAs in human health and diseases have been investigated since their discovery in mammalian cells approximately twelve years ago. Recent studies have shown that microRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. miR-146 (146a and 146b) and miR-155 are among the most studied microRNAs for their multiple roles in the control of the innate and adaptive immune processes and for their regulative and oncogenic role in some tumors. In addition to the vital role of miRNA in co-ordinating the appropriate behaviour of the immune system, miRNA is also capable of acting as an intracellular immune mediator. In this way, microRNAs can recognize viral RNA and down-modulate viral RNA stability and translation. Furthermore, when microRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity. Many of these microRNAs are currently under investigation as biomarkers or therapeutic options in a range of diseases. In many cases, miRNA expression patterns have been correlated with clinical and/or pathological parameters of the cancer. The purpose of this review is to provide an overview of the functions of microRNAs involved in the development of the immune system. In addition, their pathological roles when their expression is dysregulated and developments of miRNA-based therapeutics will be highlighted.

Keywords: microRNAs; immune system
REFERENCES:
  1. Wijnhoven BP, Michael MZ, Watson DI. MicroRNAs and cancer. Br J Surg. 2007;94(1): 23-30. [Crossref]  [PubMed] 
  2. Saydam F, Degirmenci I, Gunes HV. [MicroRNAs and cancer]. Dicle Medical Journal. 2011;38(1):113-20.
  3. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11(3):228-34. [Crossref]  [PubMed] 
  4. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-54. [Crossref] 
  5. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215-33. [Crossref]  [PubMed]  [PMC] 
  6. Raisch J, Darfeuille-Michaud A, Nguyen HT. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol. 2013;19(20):2985-96. [Crossref]  [PubMed]  [PMC] 
  7. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18 (10):997-1006. [Crossref]  [PubMed] 
  8. Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PloS One. 2012;7(3):e30679. [Crossref]  [PubMed]  [PMC] 
  9. Li L, Zhu D, Huang L, Zhang J, Bian Z, Chen X, et al. Argonaute 2 complexes selectively protect the circulating microRNAs in cell-secreted microvesicles. PloS One. 2012;7(10):e46957. [Crossref]  [PubMed]  [PMC] 
  10. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3-20.e6. [Crossref] 
  11. Akdis CA. Therapies for allergic inflammation: refining strategies to induce tolerance. Nat Med. 2012;18(5):736-49. [Crossref]  [PubMed] 
  12. Kumarswamy R, Volkmann I, Thum T. Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011;8(5):706-13. [Crossref]  [PubMed]  [PMC] 
  13. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 2010;39(4):493-506. [Crossref]  [PubMed]  [PMC] 
  14. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ, Ruan Q, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11(2):141-7. [Crossref]  [PubMed] 
  15. Rebane A, Akdis CA. MicroRNAs in allergy and asthma. Curr Allergy Asthma Rep. 2014;14(4):424. [Crossref]  [PubMed] 
  16. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33): 12481-6. [Crossref]  [PubMed]  [PMC] 
  17. Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D. NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci U S A. 2011; 108(22):9184-9. [Crossref]  [PubMed]  [PMC] 
  18. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208(6):1189-201. [Crossref]  [PubMed]  [PMC] 
  19. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010;142(6):914-29. [Crossref]  [PubMed]  [PMC] 
  20. Guo Q, Zhang J, Li J, Zou L, Zhang J, Xie Z, et al. Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells. Blood. 2013;121(24):4875-83. [Crossref]  [PubMed] 
  21. Wang P, Hou J, Lin L, Wang C, Liu X, Li D, et al. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol. 2010;185(10):6226-33. [Crossref]  [PubMed] 
  22. Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol. 2013;13(9):666-78. [Crossref]  [PubMed]  [PMC] 
  23. de Yebenes VG, Bartolome-Izquierdo N, Ramiro AR. Regulation of B-cell development and function by microRNAs. Immunol Rev. 2013;253(1):25-39. [Crossref]  [PubMed]  [PMC] 
  24. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17(1):1-14. [Crossref]  [PubMed] 
  25. Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009;113(19):4720-8. [Crossref]  [PubMed]  [PMC] 
  26. O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci U S A. 2009;106(17):7113-8. [Crossref]  [PubMed]  [PMC] 
  27. O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205(3):585-94. [Crossref]  [PubMed]  [PMC] 
  28. Fontana L, Pelosi E, Greco P, Racanicchi S, Testa U, Liuzzi F, et al. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat Cell Biol. 2007;9(7):775-87. [Crossref]  [PubMed] 
  29. Rosa A, Ballarino M, Sorrentino A, Sthandier O, De Angelis FG, Marchioni M, et al. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc Natl Acad Sci U S A. 2007;104(50):19849-54. [Crossref]  [PubMed]  [PMC] 
  30. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123(5):819-31. [Crossref]  [PubMed] 
  31. O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604-9. [Crossref]  [PubMed]  [PMC] 
  32. Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci U S A. 2009;106(13):5282-7. [Crossref]  [PubMed]  [PMC] 
  33. Ceppi M, Pereira PM, Dunand-Sauthier I, Barras E, Reith W, Santos MA, et al. MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci U S A. 2009;106(8):2735-40. [Crossref]  [PubMed]  [PMC] 
  34. Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol. 2008;9(9):1065-73. [Crossref]  [PubMed] 
  35. Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O. Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe. 2009;5(4):376-85. [Crossref]  [PubMed] 
  36. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, et al. Host immune system gene targeting by a viral miRNA. Science. 2007;317(5836):376-81. [Crossref]  [PubMed]  [PMC] 
  37. Merkerova M, Belickova M, Bruchova H. Differential expression of microRNAs in hematopoietic cell lineages. Eur J Haematol. 2008;81(4):304-10. [Crossref]  [PubMed] 
  38. Cobb BS, Nesterova TB, Thompson E, Hertweck A, O'Connor E, Godwin J, et al. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J Exp Med. 2005;201(9):1367-73. [Crossref]  [PubMed]  [PMC] 
  39. Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K. Aberrant T cell differentiation in the absence of Dicer. J Exp Med. 2005;202(2):261-9. [Crossref]  [PubMed]  [PMC] 
  40. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol. 2008;9(4):405-14. [Crossref]  [PubMed]  [PMC] 
  41. O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111-22. [Crossref]  [PubMed] 
  42. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316(5824):604-8. [Crossref]  [PubMed] 
  43. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316(5824):608-11. [Crossref]  [PubMed]  [PMC] 
  44. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252-9. [Crossref]  [PubMed] 
  45. Chong MM, Rasmussen JP, Rudensky AY, Littman DR. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med. 2008;205(9): 2005-17. [Crossref]  [PubMed]  [PMC] 
  46. Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008;205(9):1993-2004. [Crossref]  [PubMed]  [PMC] 
  47. Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, Cook T, et al. A role for Dicer in immune regulation. J Exp Med. 2006;203(11): 2519-27. [Crossref]  [PubMed]  [PMC] 
  48. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83-6. [Crossref]  [PubMed] 
  49. Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci U S A. 2007;104(17):7080-5. [Crossref]  [PubMed]  [PMC] 
  50. Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, et al. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007;131(1):146-59. [Crossref]  [PubMed] 
  51. Gebeshuber CA, Zatloukal K, Martinez J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep. 2009;10(4):400-5. [Crossref]  [PubMed]  [PMC] 
  52. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99(24):15524-9. [Crossref]  [PubMed]  [PMC] 
  53. Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009;60:167-79. [Crossref]  [PubMed] 
  54. Mi S, Lu J, Sun M, Li Z, Zhang H, Neilly MB, et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci U S A. 2007;104(50):19971-6. [Crossref]  [PubMed]  [PMC] 
  55. Roehle A, Hoefig KP, Repsilber D, Thorns C, Ziepert M, Wesche KO, et al. MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas. Br J Haematol. 2008;142(5):732-44. [Crossref]  [PubMed] 
  56. Zenz T, Mohr J, Eldering E, Kater AP, Buhler A, Kienle D, et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood. 2009;113(16):3801-8. [Crossref]  [PubMed] 
  57. Pigazzi M, Manara E, Baron E, Basso G. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res. 2009;69(6):2471-8. [Crossref]  [PubMed] 
  58. O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci U S A. 2009;106(17):7113-8. [Crossref]  [PubMed]  [PMC] 
  59. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12(5):457-66. [Crossref]  [PubMed] 
  60. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009;113 (25):6411-8. [Crossref]  [PubMed]  [PMC] 
  61. Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10(4):R101. [Crossref]  [PubMed]  [PMC] 
  62. Otaegui D, Baranzini SE, Arma-anzas R, Calvo B, Mu-oz-Culla M, Khankhanian P, et al. Differential micro RNA expression in PBMC from multiple sclerosis patients. PloS One. 2009;4(7):e6309. [Crossref]  [PubMed]  [PMC] 
  63. Qin HB, Xu B, Mei JJ, Li D, Liu JJ, Zhao DY, et al. Inhibition of miRNA-221 suppresses the airway inflammation in asthma. Inflammation. 2012;35(4):1595-9. [Crossref]  [PubMed] 
  64. Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc Natl Acad Sci U S A. 2009;106(44): 18704-9. [Crossref]  [PubMed]  [PMC] 
  65. Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK. Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm Med. 2011;11(1):29. [Crossref]  [PubMed]  [PMC] 
  66. Lu TX, Rothenberg ME. Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J Allergy Clin Immunol. 2013;132 (1):3-13. [Crossref]  [PubMed]  [PMC] 
  67. Sonkoly E, Janson P, Majuri ML, Savinko T, Fyhrquist N, Eidsmo L, et al. MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J Allergy and Clin Immunol. 2010;126(3):581-9.e1-20. [Crossref]  [PubMed] 
  68. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199(11):1567-75. [Crossref]  [PubMed]  [PMC] 
  69. Sonkoly E, Wei T, Janson PC, Saaf A, Lundeberg L, Tengvall-Linder M, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PloS One. 2007;2(7):e610. [Crossref]  [PubMed]  [PMC] 
  70. Xu N, Brodin P, Wei T, Meisgen F, Eidsmo L, Nagy N, et al. MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2. J Invest Dermatol. 2011;131(7):1521-9. [Crossref]  [PubMed] 
  71. Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327(5962):198-201. [Crossref]  [PubMed]  [PMC] 
  72. Bader AG. miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet. 2012;3:120. [Crossref]  [PubMed]  [PMC] 
  73. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12(11):847-65. [Crossref]  [PubMed]  [PMC] 
  74. Kanasty RL, Whitehead KA, Vegas AJ, Anderson DG. Action and reaction: the biological response to siRNA and its delivery vehicles. Mol Ther. 2012;20(3):513-24. [Crossref]  [PubMed]  [PMC] 

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4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com