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Increased IL18 mRNA levels in peripheral artery disease and its association with triglyceride and LDL cholesterol levels: a pilot study

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Abstract

Peripheral artery disease (PAD) typically refers to lower limb vessel ischemia caused by atherosclerotic stenosis of lower extremity arteries. IL18 is a pleiotropic pro-inflammatory cytokine reported to function as an inflammatory biomarker in cardiovascular diseases. IL18 activity is balanced by high-affinity naturally occurring IL18-binding protein (IL18BP). This study aimed to determine whether IL18, IL18 BP mRNA levels and −137 G/C (rs187238) polymorphism, which was previously associated with IL18 gene transcriptional activity, were associated with PAD etiology. IL18, IL18BP mRNA levels from peripheral blood mononuclear cells and −137 G/C (rs187238) polymorphism were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and RT-PCR, respectively, in 55 PAD patients (26 aorta-iliac, 29 femoro-popliteal) and 61 disease-free controls. IL18 mRNA levels were increased in PAD patients compared with healthy controls (p = 0.09); however, did not reach a statistical significant level, also did not significantly differ between aorta-iliac and femoro-popliteal occlusive PAD subgroups (p = 0.285). However, IL18BP mRNA levels were significantly lower in PAD group compared with controls (p < 0.001). Genotype frequencies of rs187238 polymorphism did not significantly differ between PAD patients and controls (p = 0.385). IL18 mRNA levels were significantly correlated with triglycerides and LDL cholesterol levels in PAD patients (p = 0.003, p = 0.014, respectively). HDL cholesterol levels were negatively correlated with IL18 mRNA levels in controls (p = 0.05). This report is a preliminary study to show an association between IL18, IL18BP mRNA levels and PAD and suggests that the IL18 gene may have a significant relationship with triglyceride and LDL cholesterol levels in PAD patients.

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References

  1. Selvin E, Erlinger TP (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 110(6):738–743

    Article  PubMed  Google Scholar 

  2. Veith FJ, Haimovici H (1996) Vascular surgery. Blackwell Science Inc, USA, pp 605–631

    Google Scholar 

  3. Gensler SW, Haimovici H, Hoffert P, Steinman C, Beneventano TC (1965) Study of vascular lesions in diabetic, non-diabetic patients. Arch Surg 91:617–621

    Article  CAS  PubMed  Google Scholar 

  4. Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91

    Article  CAS  PubMed  Google Scholar 

  5. Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12:204–212

    Article  CAS  PubMed  Google Scholar 

  6. Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  7. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dinarello CA (2006) Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83:447S–455S

    CAS  PubMed  Google Scholar 

  9. Reddy P (2004) Interleukin-18: recent advances. Curr Opin Hematol 11:405–410

    Article  CAS  PubMed  Google Scholar 

  10. Conti B, Jahng JW, Tinti C, Son JH, Joh TH (1997) Induction of interferon-gamma inducing factor in the adrenal cortex. J Biol Chem 272:2035–2037

    Article  CAS  PubMed  Google Scholar 

  11. Conti B, Sugama S, Kim Y, Tinti C, Kim H, Baker H, Volpe B, Attardi B, Joh T (2000) Modulation of IL-18 production in the adrenal cortex following acute ACTH or chronic corticosterone treatment. Neuroimmunomodulation 8:1–7

    Article  CAS  PubMed  Google Scholar 

  12. Seta Y, Kanda T, Tanaka T, Arai M, Sekiguchi K, Yokoyama T, Kurimoto M, Tamura J, Kurabayashi M (2000) Interleukin-18 in acute myocardial infarction. Heart 84:668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A (2001) Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 89:E41–E45

    Article  CAS  PubMed  Google Scholar 

  14. Mallat Z, Corbaz A, Scoazec A, Besnard S, Leseche G, Chvatchko Y, 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 

  15. Dinarello CA, Novick D, Kim S, Kaplanski G (2013) Interleukin-18 and IL-18 binding protein. Front Immunol 4:289

    PubMed  PubMed Central  Google Scholar 

  16. Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR (2014) IL-1β and IL-18: inflammatory markers or mediators of hypertension? Br J Pharmacol 171(24):5589–5602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. O’Brien LC, Mezzaroma E, Van Tassell BW, Marchetti C, Carbone S, Abbate A, Toldo S (2014) Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure. Mol Med 20:221–229

    PubMed  PubMed Central  Google Scholar 

  18. Novick D, Kim S, Kaplanski G, Dinarello CA (2013) Interleukin-18, more than a Th1 cytokine. Semin Immunol 25(6):439–448

    Article  CAS  PubMed  Google Scholar 

  19. Liang XH, Cheung W, Heng CK, de Wang Y (2005) Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study. Biochem Biophys Res Commun 338:736–741

    Article  CAS  PubMed  Google Scholar 

  20. Arimitsu J, Hirano T, Higa S, Kawai M, Naka T, Ogata A, Shima Y, Fujimoto M, Yamadori T, Hagiwara K, Ohgawara T, Kuwabara Y, Kawase I, Tanaka T (2006) IL-18 gene polymorphisms affect IL-18 production capability by monocytes. Biochem Biophys Res Commun 342:1413–1416

    Article  CAS  PubMed  Google Scholar 

  21. Giedraitis V, He B, Huang WX, Hillert J (2001) Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 112:146–152

    Article  CAS  PubMed  Google Scholar 

  22. http://www.rosalindfranklin.edu/Portals/6/Documents/Chandran%20Lab%20PBMC%20Isolation.pdf. Accessed 24 Mar 2015

  23. Opstad TB, Pettersen AÅ, Arnesen H, Seljeflot I (2011) Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an observational study. Cardiovasc Diabetol 10:110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pei F, Han Y, Zhang X, Yan C, Huang M, Huang L, Kang J (2009) Association of interleukin-18 gene promoter polymorphisms with risk of acute myocardial infarction in northern Chinese Han population. Clin Chem Lab Med 47:523–529

    Article  CAS  PubMed  Google Scholar 

  25. Liu W, Tang Q, Jiang H, Ding X, Liu Y, Zhu R, Tang Y, Li B, Wei M (2009) Promoter polymorphism of interleukin-18 in angiographically proven coronary artery disease. Angiology 60:180–185

    Article  PubMed  Google Scholar 

  26. Zhang N, Yu JT, Yu NN, Lu RC, Ma T, Wang ND, Miao D, Song JH, Tan L (2010) Interleukin-18 promoter polymorphisms and risk of ischemic stroke. Brain Res Bull 81(6):590–594

    Article  CAS  PubMed  Google Scholar 

  27. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U (2002) Expression of Interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 195:245–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hernesniemi JA, Heikkilä A, Raitakari OT, Kähönen M, Juonala M, Hutri-Kähönen N, Marniemi J, Viikari J, Lehtimäki T (2010) Interleukin-18 gene polymorphism and markers of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study. Ann Med 42(3):223–230

    Article  CAS  PubMed  Google Scholar 

  29. Sugiura T, Yoshikawa D, Ishii H, Suzuki S, Kumagai S, Inoue Y, Okumura S, Isobe S, Hayashi M, Ando H, Amano T, Murohara T (2014) Relation of omega-3 fatty acid and C-reactive protein to peripheral artery disease in patients with coronary artery disease. Heart Vessels 29(4):449–455

    Article  PubMed  Google Scholar 

  30. Jefferis BJ, Papacosta O, Owen CG, Wannamethee SG, Humphries SE, Woodward M, Lennon LT, Thomson A, Welsh P, Rumley A, Lowe GD, Whincup PH (2011) Interleukin 18 and coronary heart disease: prospective study and systematic review. Atherosclerosis 217:227–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, Rupprecht HJ, Investigators AtheroGene (2002) Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106:24–30

    Article  CAS  PubMed  Google Scholar 

  32. Blankenberg S, Luc G, Ducimetiere P, Arveiler D, Ferrieres J, Amouyel P, Evans A, Cambien F, Tiret L, PRIME Study Group (2003) Interleukin-18 and the risk of coronary heart disease in European men: the prospective epidemiological study of myocardial infarction (PRIME). Circulation 108:2453–2459

    Article  CAS  PubMed  Google Scholar 

  33. Hulthe J, McPheat W, Samnegård A, Tornvall P, Hamsten A, Eriksson P, Williams M, Ann S (2006) Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. Atherosclerosis 188:450–454

    Article  CAS  PubMed  Google Scholar 

  34. Kaneko H, Yajima J, Oikawa Y, Tanaka S, Fukamachi D, Suzuki S, Sagara K, Otsuka T, Matsuno S, Funada R, Kano H, Uejima T, Koike A, Nagashima K, Kirigaya H, Sawada H, Aizawa T, Yamashita T (2014) Effects of statin treatment in patients with coronary artery disease and chronic kidney disease. Heart Vessels 29(1):21–28

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Part of this study was supported by Scientific Research Projects Coordination Unit of Istanbul University, Project number 25693. The preliminary findings of this study were presented at the 13th National Medical Biology and Genetics Congress, October 27–30, 2013, Aydin, Turkey, and at 22nd Annual Meeting of the Asian Society for Cardiovascular and Thoracic Surgery, April 03–06, 2014, Istanbul, Turkey.

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Correspondence to Serkan Burc Deser.

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S. B. Deser and B. Bayoglu contributed equally to this work.

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Deser, S.B., Bayoglu, B., Besirli, K. et al. Increased IL18 mRNA levels in peripheral artery disease and its association with triglyceride and LDL cholesterol levels: a pilot study. Heart Vessels 31, 976–984 (2016). https://doi.org/10.1007/s00380-015-0753-2

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  • DOI: https://doi.org/10.1007/s00380-015-0753-2

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