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Elevated levels of IL-6 and IL-9 in the sera of patients with AAA do not correspond to their production by peripheral blood mononuclear cells

Artery Research volume 21, pages 43–52 (2018)Cite this article

Abstract

Background

Abdominal Aortic Aneurysm (AAA) is the stable local dilatation of abdominal aorta. AAA is an inflammatory condition in which cytokines may play a pathogenic role.

Methods

Peripheral Blood Mononuclear cells (PBMCs) were isolated from 5 men, with confirmed diagnosis of AAA and aortic dilation greater than 5.5 cm, and 5 men with normal/ insignificant angiography, CT-Scan and Ultrasonography results. The supernatant of PBMCs, rested overnight in RPMI containing 10%-FBS, removed to measure IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ and TNF-α using a commercial fluorescent-labeled bead assay.

Results

The mean serum IL-6 and IL-9 levels were significantly higher in patients than controls (P = 0.007 and P = 0.007, respectively). PBMCs from patients produced lower levels of IL-6 and IL-9 compared to controls but the differences were not significant. While serum TNF-α level was not different between groups, its production by PBMCs of patients was significantly lower than controls (P = 0.047). The mean serum levels of IL-10 and IFN-γ in patients were marginally higher than controls (P = 0.055, P = 0.055, respectively). Mean serum IL-2 level was not different between the groups but its production by PBMCs of patients was significantly higher than the control group (P = 0.047).

Conclusions

Our study showed alteration in the levels of cytokines from inflammatory, Th1, Th2 and Th17 subtypes in the sera of patients with AAA. The production of IL-6, IL-9, IFN-γ and IL-10, however, was not solely attributed to the PBMCs. Therefore, participation of other cells in the tissue or blood should be considered in their production.

References

  1. Curci JA, Thompson RW. Variable induction of experimental abdominal aortic aneurysms with different preparations of porcine pancreatic elastase. J Vasc Surg 1999;29:385.

    Google Scholar 

  2. Hirsch A, Haskal Z, Hertzer N, Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines. ACC/AHA guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA task force on practice guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease)—summary of recommendations. J Vasc Interv Radiol 2006;17:1383–97.

    Google Scholar 

  3. Hinterseher I, Tromp G, Kuivaniemi H. Genes and abdominal aortic aneurysm. Ann Vasc Surg 2011;25:388–412.

    Google Scholar 

  4. Sidloff D, Stather P, Dattani N, Bown M, Thompson J, Sayers R, et al. Aneurysm global epidemiology study: public health measures can further reduce abdominal aortic aneurysm mortality. Circulation 2014;129(7):747–53.

    Google Scholar 

  5. Kuivaniemi H, Elmore JR. Opportunities in abdominal aortic aneurysm research: epidemiology, genetics, and pathophysiology. Ann Vasc Surg 2012;26:862–70.

    Google Scholar 

  6. Kuivaniemi H, Sakalihasan N, Lederle FA, Jones GT, Defraigne J-O, Labropoulos N, et al. New insights into aortic diseases: a report from the third international meeting on aortic diseases (IMAD3). Aorta 2013;1:23.

    Google Scholar 

  7. Svensjö S, Björck M, Gürtelschmid M, Gidlund KD, Hellberg A, Wanhainen A. Low prevalence of abdominal aortic aneurysm among 65-year-old Swedish men indicates a change in the epidemiology of the disease. Circulation 2011;124:1118–23.

    Google Scholar 

  8. Sidney S, Rosamond WD, Howard VJ, Luepker RV. The “heart disease and stroke statistics—2013 update” and the need for a national cardiovascular surveillance system. Am Heart Assoc 2013;127(1):21–3.

    Google Scholar 

  9. Shirani S, Shakiba M, Soleymanzadeh M, Bakhshandeh H, Esfandbod M. Ultrasonographic screening for abdominal aortic aneurysms in Iranian candidates for coronary artery bypass graft surgery. Arch Iran Med 2009;12:383–8.

    Google Scholar 

  10. Lau PP, Li L, Merched AJ, Zhang AL, Ko KW, Chan L. Nicotine induces proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis in low-density lipoprotein receptor−/− mice. Arterioscler Thromb Vasc Biol 2006;26:143–9.

    Google Scholar 

  11. Stolle K, Berges A, Lietz M, Lebrun S, Wallerath T. Cigarette smoke enhances abdominal aortic aneurysm formation in angiotensin II-treated apolipoprotein E-deficient mice. Toxicol Lett 2010;199:403–9.

    Google Scholar 

  12. Ailawadi G, Eliason JL, Upchurch GR. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg 2003; 38:584–8.

    Google Scholar 

  13. Kono H, Kimura Y, Latz E. Inflammasome activation in response to dead cells and their metabolites. Curr Opin Immunol 2014; 30:91–8.

    Google Scholar 

  14. Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A. Involvement of the renin–angiotensin system in abdominal and thoracic aortic aneurysms. Clin Sci 2012;123:531–43.

    Google Scholar 

  15. Koltsova EK, Garcia Z, Chodaczek G, Landau M, McArdle S, Scott SR, et al. Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis. J Clin Investig 2012; 122:3114.

  16. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:2311–6.

    Google Scholar 

  17. Koch AE, Haines GK, Rizzo RJ, Radosevich JA, Pope RM, Robinson PG, et al. Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol 1990;137:1199.

    Google Scholar 

  18. Vorp DA, Lee PC, Wang DH, Makaroun MS, Nemoto EM, Ogawa S, et al. Association of intraluminal thrombus in abdominal aortic aneurysm with local hypoxia and wall weakening. J Vasc Surg 2001;34:291–9.

    Google Scholar 

  19. Shimizu K, Mitchell RN, Libby P. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2006;26:987–94.

    Google Scholar 

  20. Juvonen J, Surcel H-M, Satta J, Teppo A-M, Bloigu A, Syrjälä H, et al. Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1997;17:2843–7.

    Google Scholar 

  21. Schönbeck U, Sukhova GK, Gerdes N, Libby P. TH2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol 2002;161:499–506.

    Google Scholar 

  22. Lindeman JH, Abdul-Hussien H, Schaapherder AF, Bockel JHV, Thüsen JHVD, Roelen DL, et al. Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL+6-and IL-8-dominated inflammatory responses prevail in the human aneurysm. Clin Sci 2008;114:687–97.

    Google Scholar 

  23. Carmeliet P, Moons L, Lijnen R, Baes M, Lemaitre V, Tipping P, et al. Urokinase-generated plasmin activates matrix metal-loproteinases during aneurysm formation. Nat Genet 1997;17: 439–44.

    Google Scholar 

  24. Libby P, Sukhova G, Lee RT, Galis ZS. Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J Cardiovasc Pharmacol 1995;25:S9–12.

    Google Scholar 

  25. Greaves DR, Häkkinen T, Lucas AD, Liddiard K, Jones E, Quinn CM, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus-and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2001; 21:923–9.

    Google Scholar 

  26. Lin Y-z, Wu B-w, Lu Z-d, Huang Y, Shi Y, Liu H, et al. Circulating Th22 and Th9 levels in patients with acute coronary syndrome. Mediat Inflamm 2013;2013.

  27. Gregersen I, Skjelland M, Holm S, Holven KB, Krogh-Sørensen K, Russell D, et al. Increased systemic and local interleukin 9 levels in patients with carotid and coronary atherosclerosis. PLoS One 2013;8:e72769.

  28. Sharma AK, Lu G, Jester A, Johnston WF, Zhao Y, Hajzus VA, et al. Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. Circulation 2012;126:S38–45.

    Google Scholar 

  29. Ait-Oufella H, Wang Y, Herbin O, Bourcier S, Potteaux S, Joffre J, et al. Natural regulatory T cells limit angiotensin II–induced aneurysm formation and rupture in mice. Arterioscler Thromb Vasc Biol 2013;33:2374–9.

    Google Scholar 

  30. Davis VA, Persidskaia RN, Baca-Regen LM, Fiotti N, Halloran BG, Baxter BT. Cytokine pattern in aneurysmal and occlusive disease of the aorta. J Surg Res 2001;101:152–6.

    Google Scholar 

  31. Wallinder J, Skagius E, Bergqvist D, Henriksson AE. Early inflammatory response in patients with ruptured abdominal aortic aneurysm. Vasc Endovasc Surg 2010;44:32–5.

    Google Scholar 

  32. Whitman SC, Ravisankar P, Elam H, Daugherty A. Exogenous interferon-γ enhances atherosclerosis in apolipoprotein E−/− mice. Am J Pathol 2000;157:1819–24.

    Google Scholar 

  33. Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-g genes. Science 1993;259(5102): 1739–41.

    Google Scholar 

  34. Galle C, Schandene L, Stordeur P, Peignois Y, Ferreira J, Wautrecht JC, et al. Predominance of type 1 CD4+ T cells in human abdominal aortic aneurysm. Clin Exp Immunol 2005; 142:519–27.

    Google Scholar 

  35. Gerthoffer WT, Singer CA. Secretory functions of smooth muscle: cytokines and growth factors. Mol Interv 2002;2:447.

    Google Scholar 

  36. Vernier A, Diab M, Soell M, Haan-Archipoff G, Beretz A, Wachsmann D, et al. Cytokine production by human epithelial and endothelial cells following exposure to oral viridans streptococci involves lectin interactions between bacteria and cell surface receptors. Infect Immun 1996;64:3016–22.

    Google Scholar 

  37. Xiong W, MacTaggart J, Knispel R, Worth J, Persidsky Y, Baxter BT. Blocking TNF-α attenuates aneurysm formation in a murine model. J Immunol 2009;183:2741–6.

    Google Scholar 

  38. Van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, et al. Age-associated defect in human TLR–1/2 function. J Immunol 2007;178:970–5.

    Google Scholar 

  39. Hamano K, Li T-S, Takahashi M, Kobayashi T, Shirasawa B, Ito H, et al. Enhanced tumor necrosis factor-α expression in small sized abdominal aortic aneurysms. World J Surg 2003;27:476–80.

    Google Scholar 

  40. Yodoi K, Yamashita T, Sasaki N, Kasahara K, Emoto T, Matsumoto T, et al. Foxp3+ regulatory T cells play a protective role in angiotensin II–induced aortic aneurysm formation in MiceNovelty and significance. Hypertension 2015;65:889–95.

    Google Scholar 

  41. Szekanecz Z, Shah MR, Pearce WH, Koch AE. Human atherosclerotic abdominal aortic aneurysms produce interleukin (IL)- 6 and interferon-gamma but not IL-2 and IL-4: the possible role for IL-6 and interferon-gamma in vascular inflammation. Inflamm Res 1994;42:159–62.

    Google Scholar 

  42. Tieu BC, Lee C, Sun H, LeJeune W, Recinos 3rd A, Ju X, et al. An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Investig 2009;119:3637.

    Google Scholar 

  43. Hartman J, Frishman WH. Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev 2014;22:147–51.

    Google Scholar 

  44. Ju X, Ijaz T, Sun H, Ray S, Lejeune W, Lee C, et al. Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17–interleukin 17 axis in C57BL/6 MiceSignificance. Arterioscler Thromb Vasc Biol 2013;33:1612–21.

    Google Scholar 

  45. Kasashima S, Kawashima A, Zen Y, Ozaki S, Kasashima F, Endo M, et al. Upregulated interleukins (IL-6, IL-10, and IL-13) in immunoglobulin G4-related aortic aneurysm patients. J Vasc Surg 2017. pii: S0741-5214(17)30354–3.

  46. Witztum JL, Binder CJ, Chou M-Y, Fogelstrand L, Hartvigsen K, Shaw PX, et al. Natural antibodies in murine atherosclerosis. Curr Drug Targets 2008;9:190–5.

    Google Scholar 

  47. Jia L, Wu C. Differentiation, regulation and function of Th9 cells. In: T helper cell differentiation and their function. Springer; 2014. p. 181–207.

  48. Zhang W, Tang T, Nie D, Wen S, Jia C, Zhu Z, et al. IL-9 aggravates the development of atherosclerosis in Apoe−/− mice. Cardiovasc Res 2015;106:453–64.

    Google Scholar 

  49. Tilson M, Fu C, Xia S, Syn D, Yoon Y, McCaffrey T. Expression of molecular messages for angiogenesis by fibroblasts from aneurysmal abdominal aorta versus dermal fibroblasts. Int J Surg Investig 2000;1:453–7.

    Google Scholar 

  50. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci 2009;106:12885–90.

    Google Scholar 

  51. Liao M, Liu C-L, Lv B-J, Zhang J-Y, Cheng L, Cheng X, et al. Plasma cytokine levels and risks of abdominal aortic aneurysms: a population-based prospective cohort study. Ann Med 2015;47:245–52.

    Google Scholar 

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Authors and Affiliations

  1. Memory T cell Laboratory, Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, P.O. Box: 71345-3119, 71348-45794, Shiraz, Iran

    Hamid Aria & Mehrnoosh Doroudchi

  2. Department of Immunology, Professor Alborzi Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

    Mehdi Kalani

  3. Department of Vascular Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Hossein Hodjati

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  1. Hamid Aria
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  2. Mehdi Kalani
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  4. Mehrnoosh Doroudchi
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Correspondence to Mehrnoosh Doroudchi.

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Aria, H., Kalani, M., Hodjati, H. et al. Elevated levels of IL-6 and IL-9 in the sera of patients with AAA do not correspond to their production by peripheral blood mononuclear cells. Artery Res 21, 43–52 (2018). https://doi.org/10.1016/j.artres.2017.12.007

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Artery Research

ISSN: 1876-4401

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