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. 2005 Dec;81(962):746–752. doi: 10.1136/pgmj.2004.029827

Helper T cells and atherosclerosis: the cytokine web

S Baidya 1, Q Zeng 1
PMCID: PMC1743411  PMID: 16344296

Abstract

There is growing evidence regarding the importance of inflammation in the pathogenesis of atherosclerosis and its ultimate progression to the clinical syndromes. Recently there has been an increasing interest in the role of helper T (Th) cells in atherosclerosis. The Th cells act with the macrophages and the dendritic cells via the various cytokines in bringing about a variety of changes thus leading to the progression of atherosclerosis. Atherosclerotic lesions have been seen to have increased expression of type 1 helper T (TH1) cells together with increased levels of the Th1 related cytokines. It is mainly the cytokines involved with Th1 functioning that seem to show a prominent effect, with the whole process centred around interferon gamma, making it seem like every pathway and the cytokines involved lead to a final common pathway of interferon gamma secretion; the increase or decrease of which dictates the progression of atherosclerosis and its final manifestation as the clinical syndromes.

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Selected References

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  1. Abbas A. K., Murphy K. M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Anguera Ignasi, Miranda-Guardiola Faustino, Bosch Xavier, Filella Xavier, Sitges Marta, Marín José Luis, Betriu Amadeu, Sanz Ginés. Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and decreased risk of coronary events in patients with unstable angina. Am Heart J. 2002 Nov;144(5):811–817. doi: 10.1067/mhj.2002.124831. [DOI] [PubMed] [Google Scholar]
  3. Barks J. L., McQuillan J. J., Iademarco M. F. TNF-alpha and IL-4 synergistically increase vascular cell adhesion molecule-1 expression in cultured vascular smooth muscle cells. J Immunol. 1997 Nov 1;159(9):4532–4538. [PubMed] [Google Scholar]
  4. Barton Gregory M., Medzhitov Ruslan. Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol. 2002 Jun;14(3):380–383. doi: 10.1016/s0952-7915(02)00343-6. [DOI] [PubMed] [Google Scholar]
  5. Biasucci L. M., Liuzzo G., Fantuzzi G., Caligiuri G., Rebuzzi A. G., Ginnetti F., Dinarello C. A., Maseri A. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999 Apr 27;99(16):2079–2084. doi: 10.1161/01.cir.99.16.2079. [DOI] [PubMed] [Google Scholar]
  6. Björkerud S., Björkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol. 1996 Aug;149(2):367–380. [PMC free article] [PubMed] [Google Scholar]
  7. Blankenberg Stefan, Luc Gérald, Ducimetière Pierre, Arveiler Dominique, Ferrières Jean, Amouyel Philippe, Evans Alun, Cambien François, Tiret Laurence, PRIME Study Group Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 2003 Oct 27;108(20):2453–2459. doi: 10.1161/01.CIR.0000099509.76044.A2. [DOI] [PubMed] [Google Scholar]
  8. Blankenberg Stefan, Tiret Laurence, Bickel Christoph, Peetz Dirk, Cambien François, Meyer Jürgen, Rupprecht Hans J., AtheroGene Investigators Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002 Jul 2;106(1):24–30. doi: 10.1161/01.cir.0000020546.30940.92. [DOI] [PubMed] [Google Scholar]
  9. Boehm U., Klamp T., Groot M., Howard J. C. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–795. doi: 10.1146/annurev.immunol.15.1.749. [DOI] [PubMed] [Google Scholar]
  10. Brand K., Page S., Rogler G., Bartsch A., Brandl R., Knuechel R., Page M., Kaltschmidt C., Baeuerle P. A., Neumeier D. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 1996 Apr 1;97(7):1715–1722. doi: 10.1172/JCI118598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brånén Lena, Hovgaard Lars, Nitulescu Mihaela, Bengtsson Eva, Nilsson Jan, Jovinge Stefan. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2004 Sep 2;24(11):2137–2142. doi: 10.1161/01.ATV.0000143933.20616.1b. [DOI] [PubMed] [Google Scholar]
  12. Caligiuri G., Paulsson G., Nicoletti A., Maseri A., Hansson G. K. Evidence for antigen-driven T-cell response in unstable angina. Circulation. 2000 Sep 5;102(10):1114–1119. doi: 10.1161/01.cir.102.10.1114. [DOI] [PubMed] [Google Scholar]
  13. Castell J. V., Andus T., Kunz D., Heinrich P. C. Interleukin-6. The major regulator of acute-phase protein synthesis in man and rat. Ann N Y Acad Sci. 1989;557:87–101. [PubMed] [Google Scholar]
  14. Del Prete G., De Carli M., Almerigogna F., Giudizi M. G., Biagiotti R., Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993 Jan 15;150(2):353–360. [PubMed] [Google Scholar]
  15. Dinarello C. A. Biologic basis for interleukin-1 in disease. Blood. 1996 Mar 15;87(6):2095–2147. [PubMed] [Google Scholar]
  16. Elliott M. J., Gamble J. R., Park L. S., Vadas M. A., Lopez A. F. Inhibition of human monocyte adhesion by interleukin-4. Blood. 1991 Jun 15;77(12):2739–2745. [PubMed] [Google Scholar]
  17. Fernandez-Botran R., Sanders V. M., Mosmann T. R., Vitetta E. S. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988 Aug 1;168(2):543–558. doi: 10.1084/jem.168.2.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Frostegård J., Ulfgren A. K., Nyberg P., Hedin U., Swedenborg J., Andersson U., Hansson G. K. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999 Jul;145(1):33–43. doi: 10.1016/s0021-9150(99)00011-8. [DOI] [PubMed] [Google Scholar]
  20. Gaston J. S., Curry A. J., Portig I., Goodall J. C., Kirkpatrick P. J. Immune responses to Chlamydia antigens in atherosclerosis. Herz. 2000 Mar;25(2):73–78. doi: 10.1007/pl00001954. [DOI] [PubMed] [Google Scholar]
  21. George J., Shoenfeld Y., Afek A., Gilburd B., Keren P., Shaish A., Kopolovic J., Wick G., Harats D. Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein-65. Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):505–510. doi: 10.1161/01.atv.19.3.505. [DOI] [PubMed] [Google Scholar]
  22. Gerdes Norbert, Sukhova Galina K., Libby Peter, Reynolds Rebecca S., Young James L., Schönbeck Uwe. 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. 2002 Jan 21;195(2):245–257. doi: 10.1084/jem.20011022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gupta S., Pablo A. M., Jiang X. c., Wang N., Tall A. R., Schindler C. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997 Jun 1;99(11):2752–2761. doi: 10.1172/JCI119465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Han Ki Hoon, Hong Kyung-Hee, Park Jae-Hyeong, Ko Jesang, Kang Duk-Hyun, Choi Kee-Joon, Hong Myeong-Ki, Park Seong-Wook, Park Seung-Jung. C-reactive protein promotes monocyte chemoattractant protein-1--mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes. Circulation. 2004 May 10;109(21):2566–2571. doi: 10.1161/01.CIR.0000131160.94926.6E. [DOI] [PubMed] [Google Scholar]
  25. Hansson G. K., Jonasson L., Holm J., Clowes M. M., Clowes A. W. Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ Res. 1988 Oct;63(4):712–719. doi: 10.1161/01.res.63.4.712. [DOI] [PubMed] [Google Scholar]
  26. Heeschen C., Hamm C. W., Bruemmer J., Simoons M. L. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol. 2000 May;35(6):1535–1542. doi: 10.1016/s0735-1097(00)00581-7. [DOI] [PubMed] [Google Scholar]
  27. Hendrix M. G., Salimans M. M., van Boven C. P., Bruggeman C. A. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol. 1990 Jan;136(1):23–28. [PMC free article] [PubMed] [Google Scholar]
  28. Huber S. A., Sakkinen P., David C., Newell M. K., Tracy R. P. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation. 2001 May 29;103(21):2610–2616. doi: 10.1161/01.cir.103.21.2610. [DOI] [PubMed] [Google Scholar]
  29. Ibrahim Ali I., Obeid Michel T., Jouma Muhidien J., Moasis Ghassan A., Al-Richane Wael L., Kindermann Ingrid, Boehm Michael, Roemer Klaus, Mueller-Lantzsch Nikolaus, Gärtner Barbara C. Detection of herpes simplex virus, cytomegalovirus and Epstein-Barr virus DNA in atherosclerotic plaques and in unaffected bypass grafts. J Clin Virol. 2005 Jan;32(1):29–32. doi: 10.1016/j.jcv.2004.06.010. [DOI] [PubMed] [Google Scholar]
  30. Ikeda U., Ikeda M., Seino Y., Takahashi M., Kano S., Shimada K. Interleukin 6 gene transcripts are expressed in atherosclerotic lesions of genetically hyperlipidemic rabbits. Atherosclerosis. 1992 Feb;92(2-3):213–218. doi: 10.1016/0021-9150(92)90280-t. [DOI] [PubMed] [Google Scholar]
  31. Inagaki Yosuke, Yamagishi Sho-ichi, Amano Shinjiro, Okamoto Tamami, Koga Kohachiro, Makita Zenji. Interferon-gamma-induced apoptosis and activation of THP-1 macrophages. Life Sci. 2002 Oct 11;71(21):2499–2508. doi: 10.1016/s0024-3205(02)02042-8. [DOI] [PubMed] [Google Scholar]
  32. Jialal Ishwarlal, Devaraj Sridevi, Venugopal Senthil K. C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension. 2004 May 17;44(1):6–11. doi: 10.1161/01.HYP.0000130484.20501.df. [DOI] [PubMed] [Google Scholar]
  33. Jonasson L., Hansson G. K., Bondjers G., Noe L., Etienne J. Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. Biochim Biophys Acta. 1990 Jun 12;1053(1):43–48. doi: 10.1016/0167-4889(90)90024-8. [DOI] [PubMed] [Google Scholar]
  34. Jonasson L., Holm J., Skalli O., Gabbiani G., Hansson G. K. Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest. 1985 Jul;76(1):125–131. doi: 10.1172/JCI111934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kanters Edwin, Pasparakis Manolis, Gijbels Marion J. J., Vergouwe Monique N., Partouns-Hendriks Iris, Fijneman Remond J. A., Clausen Björn E., Förster Irmgard, Kockx Mark M., Rajewsky Klaus. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003 Oct;112(8):1176–1185. doi: 10.1172/JCI18580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Khew-Goodall Y., Wadham C., Stein B. N., Gamble J. R., Vadas M. A. Stat6 activation is essential for interleukin-4 induction of P-selectin transcription in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1999 Jun;19(6):1421–1429. doi: 10.1161/01.atv.19.6.1421. [DOI] [PubMed] [Google Scholar]
  37. Koenig W., Sund M., Fröhlich M., Fischer H. G., Löwel H., Döring A., Hutchinson W. L., Pepys M. B. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999 Jan 19;99(2):237–242. doi: 10.1161/01.cir.99.2.237. [DOI] [PubMed] [Google Scholar]
  38. Kuo C. C., Gown A. M., Benditt E. P., Grayston J. T. Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain. Arterioscler Thromb. 1993 Oct;13(10):1501–1504. doi: 10.1161/01.atv.13.10.1501. [DOI] [PubMed] [Google Scholar]
  39. Kurt-Jones E. A., Hamberg S., Ohara J., Paul W. E., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness. J Exp Med. 1987 Dec 1;166(6):1774–1787. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Laurat E., Poirier B., Tupin E., Caligiuri G., Hansson G. K., Bariéty J., Nicoletti A. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation. 2001 Jul 10;104(2):197–202. doi: 10.1161/01.cir.104.2.197. [DOI] [PubMed] [Google Scholar]
  41. Lee T. S., Yen H. C., Pan C. C., Chau L. Y. The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):734–742. doi: 10.1161/01.atv.19.3.734. [DOI] [PubMed] [Google Scholar]
  42. Lee Y. W., Kühn H., Kaiser S., Hennig B., Daugherty A., Toborek M. Interleukin 4 induces transcription of the 15-lipoxygenase I gene in human endothelial cells. J Lipid Res. 2001 May;42(5):783–791. [PubMed] [Google Scholar]
  43. Li H., Cybulsky M. I., Gimbrone M. A., Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993 Feb;13(2):197–204. doi: 10.1161/01.atv.13.2.197. [DOI] [PubMed] [Google Scholar]
  44. Loppnow H., Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. 1990 Mar;85(3):731–738. doi: 10.1172/JCI114498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Lotz M. Interleukin-6. Cancer Invest. 1993;11(6):732–742. doi: 10.3109/07357909309046948. [DOI] [PubMed] [Google Scholar]
  46. Mallat Z., Corbaz A., Scoazec A., Besnard S., Lesèche G., Chvatchko Y., Tedgui A. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. 2001 Oct 2;104(14):1598–1603. doi: 10.1161/hc3901.096721. [DOI] [PubMed] [Google Scholar]
  47. Mallat Z., Corbaz A., Scoazec A., Graber P., Alouani S., Esposito B., Humbert Y., Chvatchko Y., Tedgui A. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res. 2001 Sep 28;89(7):E41–E45. doi: 10.1161/hh1901.098735. [DOI] [PubMed] [Google Scholar]
  48. Mallat Z., Henry P., Fressonnet R., Alouani S., Scoazec A., Beaufils P., Chvatchko Y., Tedgui A. Increased plasma concentrations of interleukin-18 in acute coronary syndromes. Heart. 2002 Nov;88(5):467–469. doi: 10.1136/heart.88.5.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Mallat Ziad, Gojova Andrea, Brun Valérie, Esposito Bruno, Fournier Nathalie, Cottrez Françoise, Tedgui Alain, Groux Hervé. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2003 Aug 11;108(10):1232–1237. doi: 10.1161/01.CIR.0000089083.61317.A1. [DOI] [PubMed] [Google Scholar]
  50. Mazzone A., De Servi S., Vezzoli M., Fossati G., Mazzucchelli I., Gritti D., Ottini E., Mussini A., Specchia G. Plasma levels of interleukin 2, 6, 10 and phenotypic characterization of circulating T lymphocytes in ischemic heart disease. Atherosclerosis. 1999 Aug;145(2):369–374. doi: 10.1016/s0021-9150(99)00104-5. [DOI] [PubMed] [Google Scholar]
  51. Micallef M. J., Ohtsuki T., Kohno K., Tanabe F., Ushio S., Namba M., Tanimoto T., Torigoe K., Fujii M., Ikeda M. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996 Jul;26(7):1647–1651. doi: 10.1002/eji.1830260736. [DOI] [PubMed] [Google Scholar]
  52. Michelsen Kathrin S., Wong Michelle H., Shah Prediman K., Zhang Wenxuan, Yano Juliana, Doherty Terence M., Akira Shizuo, Rajavashisth Tripathi B., Arditi Moshe. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004 Jul 12;101(29):10679–10684. doi: 10.1073/pnas.0403249101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mills C. D., Kincaid K., Alt J. M., Heilman M. J., Hill A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000 Jun 15;164(12):6166–6173. doi: 10.4049/jimmunol.164.12.6166. [DOI] [PubMed] [Google Scholar]
  54. Minami M., Kume N., Shimaoka T., Kataoka H., Hayashida K., Akiyama Y., Nagata I., Ando K., Nobuyoshi M., Hanyuu M. Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1796–1800. doi: 10.1161/hq1001.096652. [DOI] [PubMed] [Google Scholar]
  55. Morrow D. A., Rifai N., Antman E. M., Weiner D. L., McCabe C. H., Cannon C. P., Braunwald E. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1998 Jun;31(7):1460–1465. doi: 10.1016/s0735-1097(98)00136-3. [DOI] [PubMed] [Google Scholar]
  56. Moyer C. F., Sajuthi D., Tulli H., Williams J. K. Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. Am J Pathol. 1991 Apr;138(4):951–960. [PMC free article] [PubMed] [Google Scholar]
  57. Muhlestein J. B., Hammond E. H., Carlquist J. F., Radicke E., Thomson M. J., Karagounis L. A., Woods M. L., Anderson J. L. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol. 1996 Jun;27(7):1555–1561. doi: 10.1016/0735-1097(96)00055-1. [DOI] [PubMed] [Google Scholar]
  58. Naghavi Morteza, Libby Peter, Falk Erling, Casscells S. Ward, Litovsky Silvio, Rumberger John, Badimon Juan Jose, Stefanadis Christodoulos, Moreno Pedro, Pasterkamp Gerard. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003 Oct 7;108(14):1664–1672. doi: 10.1161/01.CIR.0000087480.94275.97. [DOI] [PubMed] [Google Scholar]
  59. Nakahira Masakiyo, Ahn Hyun-Jong, Park Woong-Ryeon, Gao Ping, Tomura Michio, Park Cheung-Seog, Hamaoka Toshiyuki, Ohta Tsunetaka, Kurimoto Masashi, Fujiwara Hiromi. Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J Immunol. 2002 Feb 1;168(3):1146–1153. doi: 10.4049/jimmunol.168.3.1146. [DOI] [PubMed] [Google Scholar]
  60. Namiki Masayuki, Kawashima Seinosuke, Yamashita Tomoya, Ozaki Masanori, Sakoda Tsuyoshi, Inoue Nobutaka, Hirata Ken-Ichi, Morishita Ryuichi, Kaneda Yasufumi, Yokoyama Mitsuhiro. Intramuscular gene transfer of interleukin-10 cDNA reduces atherosclerosis in apolipoprotein E-knockout mice. Atherosclerosis. 2004 Jan;172(1):21–29. doi: 10.1016/j.atherosclerosis.2003.08.032. [DOI] [PubMed] [Google Scholar]
  61. Napoli C., Glass C. K., Witztum J. L., Deutsch R., D'Armiento F. P., Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet. 1999 Oct 9;354(9186):1234–1241. doi: 10.1016/S0140-6736(99)02131-5. [DOI] [PubMed] [Google Scholar]
  62. Okamura H., Tsutsi H., Komatsu T., Yutsudo M., Hakura A., Tanimoto T., Torigoe K., Okura T., Nukada Y., Hattori K. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995 Nov 2;378(6552):88–91. doi: 10.1038/378088a0. [DOI] [PubMed] [Google Scholar]
  63. Palinski W., Rosenfeld M. E., Ylä-Herttuala S., Gurtner G. C., Socher S. S., Butler S. W., Parthasarathy S., Carew T. E., Steinberg D., Witztum J. L. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1372–1376. doi: 10.1073/pnas.86.4.1372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Panousis C. G., Zuckerman S. H. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1565–1571. doi: 10.1161/01.atv.20.6.1565. [DOI] [PubMed] [Google Scholar]
  65. Panousis C. G., Zuckerman S. H. Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma. J Lipid Res. 2000 Jan;41(1):75–83. [PubMed] [Google Scholar]
  66. Passoni Federico, Morelli Benedetto, Seveso Giovanni, Lazzati Luisa, Beria Gabriella, Del Rosso Gianfranco, D'Urbano Maurizio, Cafiero Francesco, Mariani Giuseppe, De Servi Stefano. Comparative short-term prognostic value of hemostatic and inflammatory markers in patients with non-ST elevation acute coronary syndromes. Ital Heart J. 2002 Jan;3(1):28–33. [PubMed] [Google Scholar]
  67. Pinderski Oslund L. J., Hedrick C. C., Olvera T., Hagenbaugh A., Territo M., Berliner J. A., Fyfe A. I. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2847–2853. doi: 10.1161/01.atv.19.12.2847. [DOI] [PubMed] [Google Scholar]
  68. Pockley A. G., Wu R., Lemne C., Kiessling R., de Faire U., Frostegård J. Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension. 2000 Aug;36(2):303–307. doi: 10.1161/01.hyp.36.2.303. [DOI] [PubMed] [Google Scholar]
  69. Pulendran B., Smith J. L., Caspary G., Brasel K., Pettit D., Maraskovsky E., Maliszewski C. R. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1036–1041. doi: 10.1073/pnas.96.3.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Reiss A. B., Awadallah N. W., Malhotra S., Montesinos M. C., Chan E. S., Javitt N. B., Cronstein B. N. Immune complexes and IFN-gamma decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages. J Lipid Res. 2001 Nov;42(11):1913–1922. [PubMed] [Google Scholar]
  71. Ridker P. M., Buring J. E., Shih J., Matias M., Hennekens C. H. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998 Aug 25;98(8):731–733. doi: 10.1161/01.cir.98.8.731. [DOI] [PubMed] [Google Scholar]
  72. Rock F. L., Hardiman G., Timans J. C., Kastelein R. A., Bazan J. F. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):588–593. doi: 10.1073/pnas.95.2.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Salonen J. T., Ylä-Herttuala S., Yamamoto R., Butler S., Korpela H., Salonen R., Nyyssönen K., Palinski W., Witztum J. L. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992 Apr 11;339(8798):883–887. doi: 10.1016/0140-6736(92)90926-t. [DOI] [PubMed] [Google Scholar]
  74. Sempowski G. D., Derdak S., Phipps R. P. Interleukin-4 and interferon-gamma discordantly regulate collagen biosynthesis by functionally distinct lung fibroblast subsets. J Cell Physiol. 1996 May;167(2):290–296. doi: 10.1002/(SICI)1097-4652(199605)167:2<290::AID-JCP13>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  75. Smith D. A., Irving S. D., Sheldon J., Cole D., Kaski J. C. Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation. 2001 Aug 14;104(7):746–749. doi: 10.1161/hc3201.094973. [DOI] [PubMed] [Google Scholar]
  76. Stary H. C., Chandler A. B., Glagov S., Guyton J. R., Insull W., Jr, Rosenfeld M. E., Schaffer S. A., Schwartz C. J., Wagner W. D., Wissler R. W. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994 May;89(5):2462–2478. doi: 10.1161/01.cir.89.5.2462. [DOI] [PubMed] [Google Scholar]
  77. Stemme S., Faber B., Holm J., Wiklund O., Witztum J. L., Hansson G. K. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3893–3897. doi: 10.1073/pnas.92.9.3893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Stemme S., Holm J., Hansson G. K. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb. 1992 Feb;12(2):206–211. doi: 10.1161/01.atv.12.2.206. [DOI] [PubMed] [Google Scholar]
  79. Sukhova G. K., Shi G. P., Simon D. I., Chapman H. A., Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998 Aug 1;102(3):576–583. doi: 10.1172/JCI181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Upadhya Subramanya, Mooteri Shanthalaxmi, Peckham Norman, Pai Ramdas G. Atherogenic effect of interleukin-2 and antiatherogenic effect of interleukin-2 antibody in apo-E-deficient mice. Angiology. 2004 May-Jun;55(3):289–294. doi: 10.1177/000331970405500308. [DOI] [PubMed] [Google Scholar]
  81. Uyemura K., Demer L. L., Castle S. C., Jullien D., Berliner J. A., Gately M. K., Warrier R. R., Pham N., Fogelman A. M., Modlin R. L. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest. 1996 May 1;97(9):2130–2138. doi: 10.1172/JCI118650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Vabulas R. M., Ahmad-Nejad P., da Costa C., Miethke T., Kirschning C. J., Häcker H., Wagner H. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001 Jun 11;276(33):31332–31339. doi: 10.1074/jbc.M103217200. [DOI] [PubMed] [Google Scholar]
  83. Vadiveloo P. K., Stanton H. R., Cochran F. W., Hamilton J. A. Interleukin-4 inhibits human smooth muscle cell proliferation. Artery. 1994;21(3):161–181. [PubMed] [Google Scholar]
  84. Whitman S. C., Ravisankar P., Elam H., Daugherty A. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. Am J Pathol. 2000 Dec;157(6):1819–1824. doi: 10.1016/s0002-9440(10)64820-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Whitman Stewart C., Ravisankar Punnaivanam, Daugherty Alan. Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res. 2002 Feb 8;90(2):E34–E38. doi: 10.1161/hh0202.105292. [DOI] [PubMed] [Google Scholar]
  86. Williams Takeyla N., Zhang Cecelia X., Game Bryan A., He Lin, Huang Yan. C-reactive protein stimulates MMP-1 expression in U937 histiocytes through Fc[gamma]RII and extracellular signal-regulated kinase pathway:: an implication of CRP involvement in plaque destabilization. Arterioscler Thromb Vasc Biol. 2003 Oct 30;24(1):61–66. doi: 10.1161/01.ATV.0000104014.24367.16. [DOI] [PubMed] [Google Scholar]
  87. Witztum J. L., Steinberg D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med. 2001 Apr-May;11(3-4):93–102. doi: 10.1016/s1050-1738(01)00111-6. [DOI] [PubMed] [Google Scholar]
  88. Wuttge Dirk M., Zhou Xinghua, Sheikine Yuri, Wågsäter Dick, Stemme Veronika, Hedin Ulf, Stemme Sten, Hansson Göran K., Sirsjö Allan. CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2004 Feb 26;24(4):750–755. doi: 10.1161/01.ATV.0000124102.11472.36. [DOI] [PubMed] [Google Scholar]
  89. Wågsäter Dick, Olofsson Peder S., Norgren Lars, Stenberg Björn, Sirsjö Allan. The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma. Biochem Biophys Res Commun. 2004 Dec 24;325(4):1187–1193. doi: 10.1016/j.bbrc.2004.10.160. [DOI] [PubMed] [Google Scholar]
  90. Xie Q. W., Kashiwabara Y., Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994 Feb 18;269(7):4705–4708. [PubMed] [Google Scholar]
  91. Xu Q., Dietrich H., Steiner H. J., Gown A. M., Schoel B., Mikuz G., Kaufmann S. H., Wick G. Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb. 1992 Jul;12(7):789–799. doi: 10.1161/01.atv.12.7.789. [DOI] [PubMed] [Google Scholar]
  92. Yamashita Haruyo, Shimada Kazunori, Seki Eriko, Mokuno Hiroshi, Daida Hiroyuki. Concentrations of interleukins, interferon, and C-reactive protein in stable and unstable angina pectoris. Am J Cardiol. 2003 Jan 15;91(2):133–136. doi: 10.1016/s0002-9149(02)03097-7. [DOI] [PubMed] [Google Scholar]
  93. Yasojima K., Schwab C., McGeer E. G., McGeer P. L. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001 Mar;158(3):1039–1051. doi: 10.1016/S0002-9440(10)64051-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Yoshimoto T., Takeda K., Tanaka T., Ohkusu K., Kashiwamura S., Okamura H., Akira S., Nakanishi K. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol. 1998 Oct 1;161(7):3400–3407. [PubMed] [Google Scholar]
  95. Zhou X., Stemme S., Hansson G. K. Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. Am J Pathol. 1996 Aug;149(2):359–366. [PMC free article] [PubMed] [Google Scholar]
  96. Zhu J., Quyyumi A. A., Rott D., Csako G., Wu H., Halcox J., Epstein S. E. Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation. 2001 Feb 27;103(8):1071–1075. doi: 10.1161/01.cir.103.8.1071. [DOI] [PubMed] [Google Scholar]
  97. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]

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