MicroRNA-155 promotes atherosclerosis-signaling pathway through targeting gene/SOCS1 and IRAKM



MiR-155 plays a role in the regulates various aspects of innate and adaptive immune response, physiological and pathological processes. Exogenous molecular control in vivo of miR-155 expression may inhibit malignant growth, viral infections, and attenuate the progression of cardiovascular diseases. Up-regulation of proinflammatory cytokines plays a central role in atherosclerosis. In this study, we investigated the role of miR-155 in regulating proinflammatory response in atherosclerosis. Hyperlipidemic C57BL/6 male mice model were fed with atherogenic-diet for 12-weeks. MiR-155 positively regulates proinflammatory cytokines and we found increased TNFα, IL-1b, IL-6 mRNA and NF-kB in hyperlipidemic mice. Furthermore, increased miR-155 levels are correlated with proinflammatory cytokine expression in hyperlipidemic mice. To understand the mechanism by which miR-155 regulates proinflammatory cytokines in atherosclerosis, we evaluated the miR-155 target genes SOCS1 and IRAKM. We found increased miR-155 and decreased expression of SOCS1 and IRAKM in hyperlipidemic mice. Interestingly inhibition of miR-155 by using a specific miR-155 silencing, inhibited proinflammatory cytokine in hyperlipidemic mice, suggesting a role of miR-155 in immune response regulation. Based on these observations, we conclude that miR-155 modulates proinflammatory response in hyperlipidemic mice via regulation of SOCS1 and IRAKM expression. Thus, modulation of miR-155 could be a strategy to regulate atherogenic diet-induced atherosclerosis where proinflammatory cytokine plays significant role in disease progression.

Keywords: Proinflammatory cytokines; Atherosclerosis; MiR-155; SOCS1; IRAKM

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

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  1. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. Et al. miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood. 2010;15:5885–5894. doi: 10.1182/blood-2010-04-280156. [PubMed]
  2. Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5' UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008;15:460–471. doi: 10.1016/j.molcel.2008.05.001. [PubMed]
  3. Fontana L, Pelosi E, Greco P, et al. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat Cell Biol. 2007;15:775–787. doi: 10.1038/ncb1613. [PubMed]
  4. Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. 2008;15:1124–1128. doi: 10.1038/nature07299. [PubMed]
  5. Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R, Papavasiliou FN. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008;15:621–629. doi: 10.1016/j.immuni.2008.03.015. [PMC free article] [PubMed]
  6. Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M. The inhibitory effect of microRN A-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum. 2011;15:1582–1590. doi: 10.1002/art.30321. . [PubMed]
  7. NG Yousif. Fibronectin promotes migration and invasion of ovarian cancer cells through up‐regulation of FAK–PI3K/Akt pathway. Cell biology international 2013; 38(1): 85-91.[PubMed]
  8. Welch JS, Ricote M, Akiyama TE, Gonzalez FJ, Glass CK. PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci U S A. 2003;100(11):6712–6717. doi: 10.1073/pnas.1031789100. [PMC free article] [PubMed]
  9. Ohlsson BG, et al. Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages. J Clin Invest. 1996;98(1):78–89. doi: 10.1172/JCI118780. [PMC free article] [PubMed]
  10. Kluiver J, Poppema S, de Jong D, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 2005;207:243–249. [PubMed]
  11. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA. 2006;103:2257–2261. [PMC free article] [PubMed]
  12. Kluiver J, Poppema S, de Jong D, Blokzijl T, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 2005;207:243–249. [PubMed]
  13. Nazari-Jahantigh M, Wei Y, Schober A. The role of microRNAs in arterial remodelling. Thromb Haemost. 2012;107(4):611–618. doi: 10.1160/TH11-12-0826. [PubMed]
  14. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341–355. doi: 10.1016/j.cell.2011.04.005. [PMC free article] [PubMed]
  15. Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res. 2000;86:131–138. [PubMed]
  16. Babaev VR, Chew JD, Ding L, Davis S, Breyer MD, Breyer RM, Oates JA, Fazio S, Linton MF. Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis. Cell Metab. 2008;8:492–501.  [PMC free article] [PubMed]
  17. Goossens P, Gijbels MJ, Zernecke A, et al. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab. 2010;12:142–153. [PubMed]
  18. Kanters E, Pasparakis M, Gijbels MJ, et al. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;112:1176–1185. [PMC free article] [PubMed]
  19. Nakano K, Egashira K, Ohtani K, Zhao G, Funakoshi K, Ihara Y, Sunagawa K. Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys. Atherosclerosis. 2007;194:309–316. [PubMed]
  20. Seimon TA, Liao X, Magallon J, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metabolism. 2010b;12:467–482. [PMC free article] [PubMed]
  21. Tabas I, Li Y, Brocia RW, Wu SW, Swenson TL, Williams KJ. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. J Biol Chem. 1993;268:20419–20432. [PubMed]
  22. Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW. A macrophage sterol-responsive network linked to atherogenesis. Cell Metab. 2010;11:125–135. [PMC free article] [PubMed]
  23. Lee TL, Yeh J, Van Waes C, Chen Z. Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas. Mol Cancer Ther 2006; 5: 8–19. PubMed/NCBI
  24. Faraoni I, Antonetti FR, Cardone J, Bonmassar E. MiR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 2009;1792:497–505.
  25. Yu HR, Chang JC, Chen RF, Chuang H, Hong KC, et al. Different antigens trigger different Th1/Th2 reactions in neonatal mononuclear cells (MNCs) relating to T-bet/GATA-3 expression. J Leukoc Biol 2003; 74: 952–958. doi: 10.1189/jlb.0902474. PubMed/NCBI
  26. Yu CR, Mahdi RR, Oh HM, Amadi-Obi A, Levy-Clarke G, et al. Suppressor of cytokine signaling-1 (SOCS1) inhibits lymphocyte recruitment into the retina and protects SOCS1 transgenic rats and mice from ocular inflammation. Invest Ophthalmol Vis Sci 2011; 52: 6978–6986. doi: 10.1167/iovs.11-7688. PubMed/NCBI
  27. Jager LD, Dabelic R, Waiboci LW, Lau K, Haider MS, et al. The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis. J Neuroimmunol 2011;232:108–118.
  28. Chen CZ, Li L, Lodish HF, Bartel DP.  MicroRNAs modulate hematopoietic lineage differentiation. Science 2004; 303: 83–86. doi: 10.1126/science.1091903.  PubMed/NCBI
  29. Nahid MA, Satoh M, Chan EK.  Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling. J Immunol 2011;186:1723–1734. doi: 10.4049/jimmunol.1002311. PubMed/NCBI
  30. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, et al. (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611.doi: 10.1126/science.1139253. PubMed/NCBI
  31. Differential activation and functional specialization of miR-146 and miR-155 in innate immune sensing Nucleic Acids Res 1 January 2013; 542-553.
  32. Calin GA, Croce CM MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6(11):857–866. CrossRefMedlineWeb of Science
  33. Kluiver J, et al. Lack of BIC and microRNA miR-155 expression in primary cases of Burkitt lymphoma. Genes Chromosomes Cancer 2006;45(2):147–153. CrossRefMedlineWeb of Science
  34. FG Al-amran, NG Yousif, XM Meng. A TLR4-MCP-1-macrophage IL-18 Cascade Plays A Major Role in Myocardial Injury and Cardiac Dysfunction After Permanent Ischemia. Journal of Surgical Research 2011;165(2):265-266.

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Review Article
DOI: http://dx.doi.org/10.18081/2333-5106/014-04/260-269
American Journal of BioMedicine 2014, Volume 2, Issue 4, pages 260-269
Received 27 April 2014; accepted October 18, 2014, Published November 15, 2014

How to cite this article
Teng JS, Andrews LT, Faraoni EH, Arranz MD, Heymans MK, Möller ML. MicroRNA-155 promotes atherosclerosis-signaling pathway through targeting gene/SOCS1 and IRAKM. American Journal of BioMedicine 2014;2(4):260-269

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

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