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The role of cytokines in the development of atherosclerosis

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Abstract

Atherosclerosis contributes to the development of many cardiovascular diseases, which remain the leading cause of death in developed countries. Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. It is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a key factor at all stages of atherosclerosis progression. Cells involved in pathogenesis of atherosclerosis were shown to be activated by soluble factors, cytokines, that strongly influence the disease development. Pro-inflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. In this review, we discuss the latest findings on the role of cytokines in the development and progression of atherosclerosis.

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Abbreviations

ApoE:

apolipoprotein E

CVDs:

cardiovascular diseases

G-CSF:

granulocyte colony-stimulating factor

ICAM-1:

intercellular adhesion molecule 1

IFN-γ:

interferon-γ

IL:

interleukin

ILCs:

innate lymphoid cells

LDLs:

lowdensity lipoproteins

MCP-1 (CCL2):

monocyte chemoattractant protein-1

NK cells:

natural killer cells

oxLDLs:

oxidized low-density lipoproteins

SMCs:

smooth muscle cells

SOCS:

suppressor of cytokine signaling

TGFβ:

transforming growth factor beta

Th cells:

T helper cells

TLR:

toll-like receptor

TNF-α:

tumor necrosis factor-alpha

Treg cells:

regulatory T cells

VCAM-1:

vascular adhesion molecule 1

References

  1. Pagidipati, N. J., and Gaziano, T. A. (2013) Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement, Circulation, 127, 749–756.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dahlof, B. (2010) Cardiovascular disease risk factors: epidemiology and risk assessment, Am. J. Cardiol., 105, 3A9A.

    Article  Google Scholar 

  3. Nagornev, V. A., and Ketlinsky, S. A. (2009) Humoral and cell immunity against atherosclerosis: the possibility of vaccine development, Med. Akad. Zh., 9, 2–15.

    Google Scholar 

  4. Galkina, E., Kadl, A., Sanders, J., Varughese, D., Sarembock, I. J., and Ley, K. (2006) Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent, J. Exp. Med., 203, 1273–1282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Galkina, E., and Ley, K. (2009) Immune and inflammatory mechanisms of atherosclerosis, Annu. Rev. Immunol., 27, 165–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Perdiguero, G. E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E. L., Crozet, L., Garner, H., Trouillet, C., De Bruijn, M. F., Geissmann, F., and Rodewald, H. R. (2015) Tissue-resident macrophages originate from yolk-sacderived erythro-myeloid progenitors, Nature, 518, 547–551.

    Article  CAS  Google Scholar 

  7. Swirski, F. K. (2014) Monocyte recruitment and macrophage proliferation in atherosclerosis, Kardiol. Pol., 72, 311–314.

    Article  PubMed  Google Scholar 

  8. Ensan, S., Li, A., Besla, R., Degousee, N. J., Cosme, J., Roufaiel, M., Shikatani, E. A., El-Maklizi, M., Williams, J. W., Robins, L., Li, C., Lewis, B., Yun, T. J., Lee, J. S., Wieghofer, P., Khattar, R., Farrokhi, K., Byrne, J., Ouzounian, M., Zavitz, C. C., Levy, G. A., Bauer, C. M., Libby, P., Husain, M., Swirski, F. K., Cheong, C., Prinz, M., Hilgendorf, I., Randolph, G. J., Epelman, S., Gramolini, A. O., Cybulsky, M. I., Rubin, B. B., and Robbins, C. S. (2016) Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth, Nat. Immunol., 17, 159–168.

    Article  CAS  PubMed  Google Scholar 

  9. Ye, Y. X., Calcagno, C., Binderup, T., Courties, G., Keliher, E. J., Wojtkiewicz, G. R., Iwamoto, Y., Tang, J., PerezMedina, C., Mani, V., Ishino, S., Johnbeck, C. B., Knigge, U., Fayad, Z. A., Libby, P., Weissleder, R., Tawakol, A., Dubey, S., Belanger, A. P., Di Carli, M. F., Swirski, F. K., Kjaer, A., Mulder, W. J., and Nahrendorf, M. (2015) Imaging macrophage and hematopoietic progenitor proliferation in atherosclerosis, Circ. Res., 117, 835–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Warnatsch, A., Ioannou, M., Wang, Q., and Papayannopoulos, V. (2015) Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis, Science, 349, 316–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Koltsova, E. K., Hedrick, C. C., and Ley, K. (2013) Myeloid cells in atherosclerosis: a delicate balance of antiinflammatory and proinflammatory mechanisms, Curr. Opin. Lipidol., 24, 371–380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Doring, Y., Drechsler, M., Soehnlein, O., and Weber, C. (2015) Neutrophils in atherosclerosis: from mice to man, Arterioscler. Thromb. Vasc. Biol., 35, 288–295.

    Article  PubMed  CAS  Google Scholar 

  13. Binder, C. J., Shaw, P. X., Chang, M. K., Boullier, A., Hartvigsen, K., Horkko, S., Miller, Y. I., Woelkers, D. A., Corr, M., and Witztum, J. L. (2005) The role of natural antibodies in atherogenesis, J. Lipid Res., 46, 1353–1363.

    Article  CAS  PubMed  Google Scholar 

  14. Tabas, I., Garcia-Cardena, G., and Owens, G. K. (2015) Recent insights into the cellular biology of atherosclerosis, J. Cell Biol., 209, 13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hansson, G. K., Libby, P., and Tabas, I. (2015) Inflammation and plaque vulnerability, J. Intern. Med., 278, 483–493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ait-Oufella, H., Taleb, S., Mallat, Z., and Tedgui, A. (2011) Recent advances on the role of cytokines in atherosclerosis, Arterioscler. Thromb. Vasc. Biol., 31, 969–979.

    Article  CAS  PubMed  Google Scholar 

  17. Szmitko, P. E., Wang, C. H., Weisel, R. D., De Almeida, J. R., Anderson, T. J., and Verma, S. (2003) New markers of inflammation and endothelial cell activation: Part I, Circulation, 108, 1917–1923.

    Article  PubMed  Google Scholar 

  18. Mallat, Z., Taleb, S., Ait-Oufella, H., and Tedgui, A. (2009) The role of adaptive T cell immunity in atherosclerosis, J. Lipid Res., 50, 364–369.

    Article  CAS  Google Scholar 

  19. Taleb, S., Tedgui, A., and Mallat, Z. (2015) IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles, Arterioscler. Thromb. Vasc. Biol., 35, 258–264.

    Article  CAS  PubMed  Google Scholar 

  20. Ranjbaran, H., Sokol, S. I., Gallo, A., Eid, R. E., Iakimov, A. O., D’Alessio, A., Kapoor, J. R., Akhtar, S., Howes, C. J., Aslan, M., Pfau, S., Pober, J. S., and Tellides, G. (2007) An inflammatory pathway of IFN-gamma production in coronary atherosclerosis, J. Immunol., 178, 592–604.

    Article  CAS  PubMed  Google Scholar 

  21. Young, J. L., Libby, P., and Schonbeck, U. (2002) Cytokines in the pathogenesis of atherosclerosis, Thromb. Haemost., 88, 554–567.

    CAS  PubMed  Google Scholar 

  22. Koltsova, E. K., Garcia, Z., Chodaczek, G., Landau, M., McArdle, S., Scott, S. R., von Vietinghoff, S., Galkina, E., Miller, Y. I., Acton, S. T., and Ley, K. (2012) Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis, J. Clin. Invest., 122, 3114–3126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Whitman, S. C., Ravisankar, P., and Daugherty, A. (2002) IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E–/–mice, J. Interferon Cytokine Res., 22, 661–670.

    Article  CAS  PubMed  Google Scholar 

  24. Harvey, E. J., and Ramji, D. P. (2005) Interferon-gamma and atherosclerosis: proor anti-atherogenic, Cardiovasc. Res., 67, 11–20.

    Article  CAS  PubMed  Google Scholar 

  25. Wuttge, D. M., Zhou, X., Sheikine, Y., Wagsater, D., Stemme, V., Hedin, U., Stemme, S., Hansson, G. K., and Sirsjo, A. (2004) CXCL16/SR-PSOX is an interferongamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions, Arterioscler. Thromb. Vasc. Biol., 24, 750–755.

    Article  CAS  PubMed  Google Scholar 

  26. Gupta, S., Pablo, A. M., Jiang, X., Wang, N., Tall, A. R., and Schindler, C. (1997) IFN-gamma potentiates atherosclerosis in ApoE knock-out mice, J. Clin. Invest., 99, 2752–2761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Whitman, S. C., Ravisankar, P., Elam, H., and Daugherty, A. (2000) Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E–/–mice, Am. J. Pathol., 157, 1819–1824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koga, M., Kai, H., Yasukawa, Yamamoto, T., Kawai, Y., Kato, S., Kusaba, K., Kai, M., Egashira, K., Kataoka, Y., and Imaizumi, T. (2007) Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice, Circ. Res., 101, 348356.

    Article  CAS  Google Scholar 

  29. Kalliolias, G. D., and Ivashkiv, L. B. (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies, Nat. Rev. Rheumatol., 12, 49–62.

    Article  CAS  PubMed  Google Scholar 

  30. Canault, M., Peiretti, F., Poggi, M., Mueller, C., Kopp, F., Bonardo, B., Bastelica, D., Nicolay, A., Alessi, M. C., and Nalbone, G. (2008) Progression of atherosclerosis in ApoE-deficient mice that express distinct molecular forms of TNF-alpha, J. Pathol., 214, 574–583.

    Article  CAS  PubMed  Google Scholar 

  31. Ohta, H., Wada, H., Niwa, T., Kirii, H., Iwamoto, N., Fujii, H., Saito, K., Sekikawa, K., and Seishima, M. (2005) Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice, Atherosclerosis, 180, 11–17.

    Article  CAS  PubMed  Google Scholar 

  32. Jacobsson, L. T., Turesson, C., Gulfe, A., Kapetanovic, M. C., Petersson, I. F., Saxne, T., and Geborek, P. (2005) Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis, J. Rheumatol., 32, 12131218.

    Google Scholar 

  33. Huber, S. A., Sakkinen, P., David, C., Newell, M. K., and Tracy, R. P. (2001) T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia, Circulation, 103, 2610–2616.

    Article  CAS  PubMed  Google Scholar 

  34. King, V. L., Cassis, L. A., and Daugherty, A. (2007) Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice, Am. J. Pathol., 171, 2040–2047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Thornhill, M. H., Kyan-Aung, U., and Haskard, D. O. (1990) IL-4 increases human endothelial cell adhesiveness for T-cells but not for neutrophils, J. Immunol., 144, 30603065.

    Google Scholar 

  36. Lee, Y. W., Kuhn, H., Hennig, B., and Toborek, M. (2000) IL-4 induces apoptosis of endothelial cells through the caspase-3-dependent pathway, FEBS Lett., 485, 122–126.

    Article  CAS  PubMed  Google Scholar 

  37. Binder, C. J., Hartvigsen, K., Chang, M. K., Miller, M., Broide, D., Palinski, W., Curtiss, M., Corr, L. K., and Witztum, J. L. (2004) IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis, J. Clin. Invest., 114, 427437.

    Article  CAS  Google Scholar 

  38. Cardilo-Reis, L., Gruber, S., Schreier, S. M., Drechsler, M., Papac-Milicevic, N., Weber, C., Wagner, O., Stangl, H., Soehnlein, O., and Binder, C. J. (2012) Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype, EMBO Mol. Med., 4, 1072–1086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chomarat, P., and Banchereau, J. (1998) Interleukin-4 and interleukin-13: their similarities and discrepancies, Int. Rev. Immunol., 17, 1–52.

    Article  CAS  PubMed  Google Scholar 

  40. Kuperman, D. A., and Schleimer, R. P. (2008) Interleukin4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma, Curr. Mol. Med., 8, 384–392.

    CAS  Google Scholar 

  41. Tedgui, A., and Mallat, Z. (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways, Physiol. Rev., 86, 515–581.

    Article  CAS  PubMed  Google Scholar 

  42. Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. K., and Kitani, A. (2006) IL-13 signaling through the IL13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis, Nat. Med., 12, 99–106.

    Article  CAS  PubMed  Google Scholar 

  43. Korn, T., Bettelli, E., Oukka, M., and Kuchroo, V. K. (2009) IL-17 and Th17 Cells, Annu. Rev. Immunol., 27, 485–517.

    Article  CAS  PubMed  Google Scholar 

  44. Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., and Littman, D. R. (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell, 126, 1121–1133.

    Article  CAS  PubMed  Google Scholar 

  45. Patel, D. D., and Kuchroo, V. K. (2015) Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions, Immunity, 43, 1040–1051.

    Article  CAS  PubMed  Google Scholar 

  46. Taleb, S., Tedgui, A., and Mallat, Z. (2010) Interleukin-17: friend or foe in atherosclerosis, Curr. Opin. Lipidol., 21, 404–408.

    Article  CAS  PubMed  Google Scholar 

  47. Xie, J. J., Wang, J., Tang, T. T., Chen, J., Gao, X. L., Yuan, J., Zhou, Z. H., Liao, M. Y., Yao, R., Yu, X., Wang, D., Cheng, Y., Liao, Y. H., and Cheng, X. (2010) The Th17/Treg functional imbalance during atherogenesis in ApoE–/–mice, Cytokine, 49, 185–193.

    Article  CAS  PubMed  Google Scholar 

  48. Ma, T., Gao, Q., Zhu, F., Guo, C., Wang, Q., Gao, F., and Zhang, L. (2013) Th17 cells and IL-17 are involved in the disruption of vulnerable plaques triggered by short-term combination stimulation in apolipoprotein E-knockout mice, Cell. Mol. Immunol., 10, 338–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Madhur, M. S., Funt, S. A., Li, L., Vinh, A., Chen, W., Lob, H. E., Iwakura, Y., Blinder, Y., Rahman, A., Quyyumi, A. A., and Harrison, D. G. (2011) Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein E-deficient mice, Arterioscler. Thromb. Vasc. Biol., 31, 1565–1572.

    Article  CAS  PubMed  Google Scholar 

  50. Danzaki, K., Matsui, Y., Ikesue, M., Ohta, D., Ito, K., Kanayama, M., Kurotaki, D., Morimoto, J., Iwakura, Y., Yagita, H., Tsutsui, H., and Uede, T. (2012) Interleukin17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice, Arterioscler. Thromb. Vasc. Biol., 32, 273–280.

    Article  CAS  PubMed  Google Scholar 

  51. Taleb, S., Romain, M., Ramkhelawon, B., Uyttenhove, C., Pasterkamp, G., Herbin, O., Esposito, B., Perez, N., Yasukawa, H., Van Snick, J., Yoshimura, A., Tedgui, A., and Mallat, Z. (2009) Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis, J. Exp. Med., 206, 2067–2077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Butcher, M. J., Gjurich, B. N., Phillips, T., and Galkina, E. V. (2012) The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment, Circ. Res., 110, 675–687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Smith, E., Prasad, K. M., Butcher, M., Dobrian, A., Kolls, J. K., Ley, K., and Galkina, E. (2010) Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice, Circulation, 121, 17461755.

    Google Scholar 

  54. Erbel, C., Chen, L., Bea, F., Wangler, S., Celik, S., Lasitschka, F., Wang, Y., Bockler, D., Katus, H. A., and Dengler, T. J. (2009) Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice, J. Immunol., 183, 8167–8175.

    Article  CAS  PubMed  Google Scholar 

  55. Gao, Q., Jiang, Y., Ma, T., Zhu, F., Gao, F., Zhang, P., Guo, C., Wang, Q., Wang, X., Ma, C., Zhang, Y., Chen, W., and Zhang, L. (2010) A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice, J. Immunol., 185, 5820–5827.

    Article  CAS  PubMed  Google Scholar 

  56. Wang, X., Ota, N., Manzanillo, P., Kates, L., ZavalaSolorio, J., Eidenschenk, C., Zhang, J., Lesch, J., Lee, W. P., Ross, J., Diehl, L., Van Bruggen, N., Kolumam, G., and Ouyang, W. (2014) Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes, Nature, 514, 237–341.

    CAS  PubMed  Google Scholar 

  57. Rattik, S., Hultman, K., Rauch, U., Soderberg, I., Sundius, L., Ljungcrantz, I., Hultgardh-Nilsson, A., Wigren, M., Bjorkbacka, H., Fredrikson, G. N., and Nilsson, J. (2015) IL-22 affects smooth muscle cell phenotype and plaque formation in apolipoprotein E knockout mice, Atherosclerosis, 242, 506–514.

    Article  CAS  PubMed  Google Scholar 

  58. Jones, L. L., and Vignali, D. A. (2011) Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily, Immunol. Res., 51, 5–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Garbers, C., Hermanns, H. M., Schaper, F., MullerNewen, G., Grotzinger, J., Rose-John, S., and Scheller, J. (2012) Plasticity and cross-talk of interleukin 6-type cytokines, Cytokine Growth Factor Rev., 23, 85–97.

    Article  CAS  PubMed  Google Scholar 

  60. Xing, Z., Gauldie, J., Cox, G., Baumann, H., Jordana, M., Lei, X. F., and Achong, M. K. (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses, J. Clin. Invest., 101, 311–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fontes, J. A., Rose, N. R., and Cihakova, D. (2015) The varying faces of IL-6: from cardiac protection to cardiac failure, Cytokine, 74, 62–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huber, S. A., Sakkinen, P., Conze, D., Hardin, N., and Tracy, R. (1999) Interleukin-6 exacerbates early atherosclerosis in mice, Arterioscler. Thromb. Vasc. Biol., 19, 23642367.

    Article  Google Scholar 

  63. Schieffer, B., Selle, T., Hilfiker, A., Hilfiker-Kleiner, D., Grote, K., Tietge, U. J., Trautwein, C., Luchtefeld, M., Schmittkamp, C., Heeneman, S., Daemen, M. J., and Drexler, H. (2004) Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis, Circulation, 110, 3493–3500.

    Article  CAS  PubMed  Google Scholar 

  64. Elhage, R., Clamens, S., Besnard, S., Mallat, Z., Tedgui, A., Arnal, J., Maret, A., and Bayard, F. (2001) Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17beta-estradiol in apolipoprotein E-deficient mice, Atherosclerosis, 156, 315320.

    Article  Google Scholar 

  65. Rose-John, S. (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6, Int. J. Biol. Sci., 8, 1237–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schuett, H., Oestreich, R., Waetzig, G. H., Annema, W., Luchtefeld, M., Hillmer, A., Bavendiek, U., von Felden, J., Divchev, D., Kempf, T., Wollert, K. C., Seegert, D., RoseJohn, S., Tietge, U. J., Schieffer, B., and Grote, K. (2012) Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice, Arterioscler. Thromb. Vasc. Biol., 32, 281–290.

    Article  CAS  PubMed  Google Scholar 

  67. Teng, M. W., Bowman, E. P., McElwee, J. J., Smyth, M. J., Casanova, J. L., Cooper, A. M., and Cua, D. J. (2015) IL12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases, Nat. Med., 21, 719–729.

    Article  CAS  PubMed  Google Scholar 

  68. Diefenbach, A., Colonna, M., and Koyasu, S. (2014) Development, differentiation, and diversity of innate lymphoid cells, Immunity, 41, 354–365.

    CAS  PubMed  Google Scholar 

  69. Abbas, A., Gregersen, I., Holm, S., Daissormont, I., Bjerkeli, V., Krohg-Sorensen, K., Skagen, K. R., Dahl, T. B., Russell, D., Almas, T., Bundgaard, D., Alteheld, L. H., Rashidi, A., Dahl, C. P., Michelsen, A. E., Biessen, E. A., Aukrust, P., Halvorsen, B., and Skjelland, M. (2015) Interleukin 23 levels are increased in carotid atherosclerosis: possible role for the interleukin 23/interleukin 17 axis, Stroke, 46, 793–799.

    Article  CAS  PubMed  Google Scholar 

  70. Davenport, P., and Tipping, P. G. (2003) The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice, Am. J. Pathol., 163, 1117–1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, T. S., Yen, H. C., Pan, C. C., and Chau, L. Y. (1999) The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice, Arterioscler. Thromb. Vasc. Biol., 19, 734–742.

    Article  CAS  PubMed  Google Scholar 

  72. Yoshida, H., and Hunter, C. A. (2015) The immunobiology of interleukin-27, Annu. Rev. Immunol., 33, 417–443.

    Article  CAS  PubMed  Google Scholar 

  73. Koltsova, E. K., Kim, G., Lloyd, K. M., Saris, C. J., Von Vietinghoff, S., Kronenberg, M., and Ley, K. (2012) IL-27 receptor limits atherosclerosis in Ldlr–/–mice, Circ. Res., 111, 1274–1285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hirase, T., Hara, H., Miyazaki, Y., Ide, N., NishimotoHazuku, A., Fujimoto, H., Saris, C. J., Yoshida, H., and Node, K. (2013) Interleukin 27 inhibits atherosclerosis via immunoregulation of macrophages in mice, Am. J. Physiol. Heart Circ. Physiol., 305, 420–429.

    Article  CAS  Google Scholar 

  75. Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg, R. S., and Vignali, D. A. (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function, Nature, 450, 566569.

    Article  CAS  Google Scholar 

  76. Collison, L. W., Delgoffe, G. M., Guy, C. S., Vignali, K. M., Chaturvedi, V., Fairweather, D., Satoskar, A. R., Garcia, K. C., Hunter, C. A., Drake, C. G., Murray, P. J., and Vignali, D. A. (2012) The composition and signaling of the IL-35 receptor are unconventional, Nat. Immunol., 13, 290–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kempe, S., Heinz, P., Kokai, E., Devergne, O., Marx, N., and Wirth, T. (2009) Epstein–Barr virus-induced gene-3 is expressed in human atheroma plaques, Am. J. Pathol., 175, 440–447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sha, X., Meng, S., Li, X., Xi, H., Maddaloni, M., Pascual, D. W., Shan, H., Jiang, X., Wang, H., and Yang, X. F. (2015) Interleukin-35 inhibits endothelial cell activation by suppressing MAPK-AP-1 pathway, J. Biol. Chem., 290, 19307–19318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dinarello, C. A. (2009) Immunological and inflammatory functions of the interleukin-1 family, Annu. Rev. Immunol., 27, 519–550.

    Article  CAS  PubMed  Google Scholar 

  80. Kirii, H., Niwa, T., Yamada, Y., Wada, H., Saito, K., Iwakura, Y., Asano, M., Moriwaki, H., and Seishima, M. (2003) Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice, Arterioscler. Thromb. Vasc. Biol., 23, 656–660.

    Article  CAS  PubMed  Google Scholar 

  81. Mills, K. H. (2008) Induction, function and regulation of IL-17-producing T cells, Eur. J. Immunol., 38, 26362649.

    Article  CAS  Google Scholar 

  82. Clarke, M. C., Talib, S., Figg, N. L., and Bennett, M. R. (2010) Vascular smooth muscle cell apoptosis induces interleukin-1-directed inflammation: effects of hyperlipidemia-mediated inhibition of phagocytosis, Circ. Res., 106, 363–372.

    Article  CAS  PubMed  Google Scholar 

  83. Sheedy, F. J., Grebe, A., Rayner, K. J., Kalantari, P., Ramkhelawon, B., Carpenter, S. B., Becker, C. E., Ediriweera, H. N., Mullick, A. E., Golenbock, D. T., Stuart, L. M., Latz, E., Fitzgerald, K. A., and Moore, K. J. (2013) CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation, Nat. Immunol., 14, 812–820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Freigang, S., Ampenberger, F., Weiss, A., Kanneganti, T. D., Iwakura, Y., Hersberger, M., and Kopf, M. (2013) Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis, Nat. Immunol., 14, 1045–1053.

    Article  CAS  PubMed  Google Scholar 

  85. Kamari, Y., Shaish, A., Shemesh, S., Vax, E., Grosskopf, I., Dotan, S., White, M., Voronov, E., Dinarello, C. A., Apte, R. N., and Harats, D. (2011) Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-Edeficient mice lacking bone marrow-derived interleukin1alpha, Biochem. Biophys. Res. Commun., 405, 197–203.

    Article  CAS  PubMed  Google Scholar 

  86. Isoda, K., Sawada, S., Ishigami, N., Matsuki, T., Miyazaki, K., Kusuhara, M., Iwakura, Y., and Ohsuzu, F. (2004) Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice, Arterioscler. Thromb. Vasc. Biol., 24, 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  87. Elhage, R., Maret, A., Pieraggi, M. T., Thiers, J. C., Arnal, J. F., and Bayard, F. (1998) Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice, Circulation, 97, 242–244.

    Article  CAS  PubMed  Google Scholar 

  88. Devlin, C. M., Kuriakose, G., Hirsch, E., and Tabas, I. (2002) Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size, Proc. Natl. Acad. Sci. USA, 99, 6280–6285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Merhi-Soussi, F., Kwak, B. R., Magne, D., Chadjichristos, C., Berti, M., Pelli, G., James, R. W., Mach, F., and Gabay, C. (2005) Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice, Cardiovasc. Res., 66, 583–593.

    Article  CAS  PubMed  Google Scholar 

  90. Mallat, Z., Corbaz, A., Scoazec, A., Besnard, S., Leseche, G., Chvatchko, Y., and Tedgui, A. (2001) Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability, Circulation, 104, 1598–1603.

    Article  CAS  PubMed  Google Scholar 

  91. Troseid, M., Seljeflot, I., and Arnesen, H. (2010) The role of interleukin-18 in the metabolic syndrome, Cardiovasc. Diabetol., 9, 11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Whitman, S. C., Ravisankar, P., and Daugherty, A. (2002) Interleukin-18 enhances atherosclerosis in apolipoprotein E–/–mice through release of interferon-gamma, Circ. Res., 90, e34-38.

    Article  Google Scholar 

  93. Mallat, Z., Corbaz, A., Scoazec, A., Graber, P., Alouani, S., Esposito, B., Humbert, Y., Chvatchko, Y., and Tedgui, A. (2001) Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability, Circ. Res., 89, e41-45.

    Article  Google Scholar 

  94. Tenger, C., Sundborger, A., Jawien, J., and Zhou, X. (2005) IL-18 accelerates atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T-cells, Arterioscler. Thromb. Vasc. Biol., 25, 791–796.

    Article  CAS  PubMed  Google Scholar 

  95. Schmitz, J., Owyang, A., Oldham, E., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., Gorman, D. M., Bazan, J. F., and Kastelein, R. A. (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T-helper type 2-associated cytokines, Immunity, 23, 479490.

    Google Scholar 

  96. Miller, A. M., Xu, D., Asquith, D. L., Denby, L., Li, Y., Sattar, N., Baker, A. H., McInnes, I. B., and Liew, F. Y. (2008) IL-33 reduces the development of atherosclerosis, J. Exp. Med., 205, 339–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. McLaren, J. E., Michael, D. R., Salter, R. C., Ashlin, T. G., Calder, C. J., Miller, A. M., Liew, F. Y., and Ramji, D. P. (2010) IL-33 reduces macrophage foam cell formation, J. Immunol., 185, 1222–1229.

    Article  CAS  PubMed  Google Scholar 

  98. Rutz, S., Wang, X., and Ouyang, W. (2014) The IL-20 subfamily of cytokines–from host defence to tissue homeostasis, Nat. Rev. Immunol., 14, 783–795.

    Article  CAS  PubMed  Google Scholar 

  99. Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A., and Hymowitz, S. G. (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease, Annu. Rev. Immunol., 29, 71–109.

    Article  CAS  PubMed  Google Scholar 

  100. Moore, K. W., De Waal Malefyt, R., Coffman, R. L., and O’Garra, A. (2001) Interleukin-10 and the interleukin-10 receptor, Annu. Rev. Immunol., 19, 683–765.

    Article  CAS  PubMed  Google Scholar 

  101. Mallat, Z., Besnard, S., Duriez, M., Deleuze, V., Emmanuel, F., Bureau, M. F., Soubrier, F., Esposito, B., Duez, H., Fievet, C., Staels, B., Duverger, N., Scherman, D., and Tedgui, A. (1999) Protective role of interleukin-10 in atherosclerosis, Circ. Res., 85, 17–24.

    Article  Google Scholar 

  102. Pinderski Oslund, L. J., Hedrick, C. C., Olvera, T., Hagenbaugh, A., Territo, M., Berliner, J. A., and Fyfe, A. I. (1999) Interleukin-10 blocks atherosclerotic events in vitro and in vivo, Arterioscler. Thromb. Vasc. Biol., 19, 28472853.

    Article  Google Scholar 

  103. Caligiuri, G., Rudling, M., Ollivier, V., Jacob, M. P., Michel, J. B., Hansson, G. K., and Nicoletti, A. (2003) Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice, Mol. Med., 9, 10–17.

    CAS  PubMed  Google Scholar 

  104. Tian, Y., Sommerville, L. J., Cuneo, A., Kelemen, S. E., and Autieri, M. V. (2008) Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia, Am. J. Pathol., 173, 901–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ellison, S., Gabunia, K., Richards, J. M., Kelemen, S. E., England, R. N., Rudic, D., Azuma, Y. T., Munroy, M. A., Eguchi, S., and Autieri, M. V. (2014) IL-19 reduces ligationmediated neointimal hyperplasia by reducing vascular smooth muscle cell activation, Am. J. Pathol., 184, 2134–2143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gabunia, K., Jain, S., England, R. N., and Autieri, M. V. (2011) Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility, Am. J. Physiol. Cell Physiol., 300, C896-906.

  107. Chen, W. Y., Cheng, B. C., Jiang, M. J., Hsieh, M. Y., and Chang, M. S. (2006) IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein Edeficient mice, Arterioscler. Thromb. Vasc. Biol., 26, 20902095.

    Google Scholar 

  108. Blobe, G. C., Schiemann, W. P., and Lodish, H. F. (2000) Role of transforming growth factor beta in human disease, N. Engl. J. Med., 342, 1350–1358.

  109. Pepper, M. S. (1997) Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity, Cytokine Growth Factor Rev., 8, 21–43.

    Article  CAS  PubMed  Google Scholar 

  110. Lutgens, E., and Daemen, M. J. (2001) Transforming growth factor-beta: a local or systemic mediator of plaque stability, Circ. Res., 89, 853–855.

    CAS  PubMed  Google Scholar 

  111. Mallat, Z., Gojova, A., Marchiol-Fournigault, C., Esposito, B., Kamate, C., Merval, R., Fradelizi, D., and Tedgui, A. (2001) Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice, Circ. Res., 89, 930934.

    Article  Google Scholar 

  112. Grainger, D. J., Mosedale, D. E., Metcalfe, J. C., and Bottinger, E. P. (2000) Dietary fat and reduced levels of TGFbeta1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions, J. Cell Sci., 113, 2355–2361.

    CAS  PubMed  Google Scholar 

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  1. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, USA

    A. R. Fatkhullina, I. O. Peshkova & E. K. Koltsova

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Original Russian Text © A. R. Fatkhullina, I. O. Peshkova, E. K. Koltsova, 2016, published in Biokhimiya, 2016, Vol. 81, No. 11, pp. 1614–1627.

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Fatkhullina, A.R., Peshkova, I.O. & Koltsova, E.K. The role of cytokines in the development of atherosclerosis. Biochemistry Moscow 81, 1358–1370 (2016). https://doi.org/10.1134/S0006297916110134

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