The IL-33/ST2 pathway: Therapeutic target and novel biomarker

Nature Reviews Drug Discovery

Volumn 7, Issue 10, 2008, Pages 827-840

  Kakkar, Rahul ^a   Lee, Richard T ^b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; CYTOKINE; CYTOKINE RECEPTOR; DECOY RECEPTOR SST2; INTERLEUKIN 1 RECEPTOR; INTERLEUKIN 33; LIGAND; PROTEIN ST2; RECEPTOR PROTEIN; ROFECOXIB; ROSIGLITAZONE; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG;

ASTHMA; ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; CARDIOVASCULAR DISEASE; CELLULAR IMMUNITY; DIAGNOSTIC VALUE; DISEASE MARKER; FIBROSIS; HEART FAILURE; HEART MUSCLE FIBROSIS; HEART PROTECTION; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INJURY; NEOPLASM; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; PROTEIN TARGETING; PROTEIN VARIANT; REVIEW; RHEUMATOID ARTHRITIS; SCAR FORMATION; SEPSIS; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION;

ANIMALS; ATHEROSCLEROSIS; BIOLOGICAL MARKERS; DISEASE PROGRESSION; DRUG DELIVERY SYSTEMS; HUMANS; INTERLEUKINS; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION;

EID: 53249113212     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2660     Document Type: Review

References (173)

1. Sims, J. E. IL-1 and IL-18 receptors, and their extended family. Curr. Opin. Immunol. 14, 117-122 (2002).
2. Tominaga, S. A putative protein of a growth specific cDNA from BALB/ c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 258, 301-304 (1989).
3. Trajkovic, V., Sweet, M. J. & Xu, D. T1/ST2 - an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 15 87-95 (2004).
4. + T cells: Induction of type 2 cytokine production by T1/ST2 cross-linking. J. Immunol. 166, 3143-3150 (2001).
5. Oshikawa, K. et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am. J. Resp. Crit. Care Med. 164, 277-281 (2001).
6. Leung, B. P., Xu, D., Culshaw, S., McInnes, I. B. & Liew, F. Y. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J. Immunol. 173, 145-150 (2004).
7. Kuroiwa, K., Arai, T., Okazaki, H., Minota, S. & Tominaga, S. Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem. Biophys. Res. Commun. 284, 1104-1108 (2001).
8. Brunner, M. et al. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med. 30, 1468-1473 (2004).
9. Barksby, H. E., Lea, S. R., Preshaw, P. M. & Taylor, J. J. The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin. Exp. Immunol. 149, 217-225 (2007).
10. Schmitz, J. et al. 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, 479-490 (2005).
11. Dinarello, C. A. An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity 23, 461-462 (2005).
12. Sanada, S. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Invest. 117, 1538-1549 (2007).
13. Miller, A. M. et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205, 339-346 (2008).
14. Januzzi, J. L. Jr et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: Results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J. Am. Coll. Cardiol. 50, 607-613 (2007).
15. Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111-115 (2000).
16. Michelsen, K. S., Doherty, T. M., Shah, P. K. & Arditi, M. TLR signaling: An emerging bridge from innate immunity to atherogenesis. J. Immunol. 173, 5901-5907 (2004).
17. Abreu, M. T. & Arditi, M. Innate immunity and toll-like receptors: clinical implications of basic science research. J. Pediatr. 144, 421-429 (2004).
18. O'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Rev. Immunol. 7, 353-364 (2007).
19. Werenskiold, A. K., Hoffmann, S. & Klemenz, R. Induction of a mitogen-responsive gene after expression of the Ha-ras oncogene in NIH 3T3 fibroblasts. Mol. Cell. Biol. 9, 5207-5214 (1989).
20. Klemenz, R., Hoffmann, S. & Werenskiold, A. K. Serum- and oncoprotein-mediated induction of a gene with sequence similarity to the gene encoding carcinoembryonic antigen. Proc. Natl Acad. Sci. USA 86, 5708-5712 (1989).
21. Werenskiold, A. K. Characterization of a secreted glycoprotein of the immunoglobulin superfamily inducible by mitogen and oncogene. Eur. J. Biochem. 204, 1041-1047 (1992).
22. Takagi, T. et al. Identification of the product of the murine ST2 gene. Biochim. Biophys. Acta 1178, 194-200 (1993).
23. Yanagisawa, K., Takagi, T., Tsukamoto, T., Tetsuka, T. & Tominaga, S. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1. FEBS Lett. 318, 83-87 (1993).
24. Iwahana, H. et al. Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells. Eur. J. Biochem. 264, 397-406 (1999).
25. Bergers, G., Reikerstorfer, A., Braselmann, S., Graninger, P. & Busslinger, M. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 13, 1176-1188 (1994).
26. Thomassen, E. et al. Role of cell type-specific promoters in the developmental regulation of T1, an interleukin 1 receptor homologue. Cell Growth Differ. 6, 179-184 (1995).
27. Gachter, T., Werenskiold, A. K. & Klemenz, R. Transcription of the interleukin-1 receptor-related T1 gene is initiated at different promoters in mast cells and fibroblasts. J. Biol. Chem. 271, 124-129 (1996).
28. Tominaga, S. et al. Presence and expression of a novel variant form of ST2 gene product in human leukemic cell line UT-7/GM. Biochem. Biophys. Res. Commun. 264, 14-18 (1999).
29. Iwahana, H. et al. Molecular cloning of the chicken ST2 gene and a novel variant form of the ST2 gene product, ST2LV. Biochim. Biophys. Acta 1681, 1-14 (2004).
30. Lohning, M. et al. T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc. Natl Acad. Sci. USA 95, 6930-6935 (1998).
31. Yanagisawa, K. et al. The expression of ST2 gene in helper T cells and the binding of ST2 protein to myeloma-derived RPMI8226 cells. J. Biochem. 121, 95-103 (1997).
32. Xu, D. et al. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J. Exp. Med. 187, 787-794 (1998).
33. Rossler, U. et al. Secreted and membrane-bound isoforms of T1, an orphan receptor related to IL-1-binding proteins, are differently expressed in vivo. Dev. Biol. 168, 86-97 (1995).
34. Kumar, S., Tzimas, M. N., Griswold, D. E. & Young, P. R. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235, 474-478 (1997).
35. Tago, K. et al. Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V. Biochem. Biophys. Res. Commun. 285, 1377-1383 (2001).
36. Kumar, S., Minnich, M. D. & Young, P. R. ST2/T1 protein functionally binds to two secreted proteins from Balb/c 3T3 and human umbilical vein endothelial cells but does not bind interleukin 1. J. Biol. Chem. 270, 27905-27913 (1995).
37. Baekkevold, E. S. et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am. J. Pathol. 163, 69-79 (2003).
38. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282-287 (2007).
39. Sharma, S. et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J. Immunol. 180, 5477-5482 (2008).
40. Gadina, M. & Jefferies, C. A. IL-33: A sheep in wolf's clothing? Sci. STKE 390, pe31 (2007).
41. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818-831 (2008).
42. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: Critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675-680 (2001).
43. Palmer, G. et al. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine 42, 358-364 (2008).
44. Chackerian, A. A. et al. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J. Immunol. 179, 2551-2555 (2007).
45. Ali, S. et al. IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc. Natl Acad. Sci. USA 104, 18660-18665 (2007).
46. Funakoshi-Tago, M. et al. TRAF6 is a critical signal transducer in IL-33 signaling pathway. Cell. Signal. 20, 1679-1686 (2008).
47. Brint, E. K. et al. Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue T1/ST2. A role for Jun N-terminal kinase in IL-4 induction. J. Biol. Chem. 277 49205-49211 (2002).
48. Brint, E. K. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature Immunol. 5, 373-379 (2004).
49. Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791-800 (2008).
50. Oshikawa, K., Yanagisawa, K., Tominaga, S. & Sugiyama, Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin. Exp. Allergy 32, 1520-1526 (2002).
51. Hayakawa, H., Hayakawa, M., Kume, A. & Tominaga, S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J. Biol. Chem. 282, 26369-26380 (2007).
52. Komai-Koma, M. et al. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37, 2779-2786 (2007).
53. Kropf, P. et al. Expression of Th2 cytokines and the stable Th2 marker ST2L in the absence of IL-4 during Leishmania major infection. Eur. J. Immunol. 29, 3621-3628 (1999).
54. Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245-248 (1993).
55. Hoshino, K. et al. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J. Exp. Med. 190, 1541-1548 (1999).
56. Townsend, M. J., Fallon, P. G., Matthews, D. J., Jolin, H. E. & McKenzie, A. N. T1/ST2-deficient mice demonstrate the importance of T1/ ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069-1076 (2000).
57. Kropf, P. et al. Identification of two distinct subpopulations of Leishmania major-specific T helper 2 cells. Infect. Immun. 70, 5512-5520 (2002).
58. + T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 158, 3539-3544 (1997).
59. Hogan, S. P. et al. A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J. Immunol. 161, 1501-1509 (1998).
60. Coyle, A. J. et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190, 895-902 (1999).
61. Lambrecht, B. N. et al. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106, 551-559 (2000).
62. Allakhverdi, Z., Smith, D. E., Comeau, M. R. & Delespesse, G. Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J. Immunol. 179, 2051-2054 (2007).
63. Moulin, D. et al. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 40, 216-225 (2007).
64. Oshikawa, K. et al. Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid. Respir. Med. 95, 532-533 (2001).
65. H2 paradigm. Nature Rev. Immunol. 4, 583-594 (2004).
66. Tajima, S. et al. ST2 gene induced by type 2 helper T cell (Th2) and proinflammatory cytokine stimuli may modulate lung injury and fibrosis. Exp. Lung Res. 33, 81-97 (2007).
67. Tajima, S., Oshikawa, K., Tominaga, S. & Sugiyama, Y. The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest 124, 1206-1214 (2003).
68. Amatucci, A. et al. Recombinant ST2 boosts hepatic Th2 response in vivo. J. Leukoc. Biol. 82, 124-132 (2007).
69. Sweet, M. J. et al. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J. Immunol. 166, 6633-6639 (2001).
70. Wynn, T. A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117, 524-529 (2007).
71. Miltenburg, A. M., van Laar, J. M., de Kuiper, R., Daha, M. R. & Breedveld, F. C. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand. J. Immunol. 35 603-610 (1992).
72. Dolhain, R. J., van der Heiden, A. N., ter Haar, N. T., Breedveld, F. C. & Miltenburg, A. M. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 39, 1961-1969 (1996).
73. Verri, W. A. Jr et al. IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc. Natl Acad. Sci. USA 105, 2723-2728 (2008).
74. Miller, A. C., Rashid, R. M. & Elamin, E. M. The "T" in trauma: The helper T-cell response and the role of immunomodulation in trauma and burn patients. J. Trauma 63, 1407-1417 (2007).
75. Oshikawa, K., Yanagisawa, K., Tominaga, S. & Sugiyama, Y. ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation. Biochem. Biophys. Res. Commun. 299, 18-24 (2002).
76. Feterowski, C. et al. Attenuated pathogenesis of polymicrobial peritonitis in mice after TLR2 agonist pre-treatment involves ST2 up-regulation. Int. Immunol. 17, 1035-1046 (2005).
77. Klemenz, R., Hoffmann, S., Jaggi, R. & Werenskiold, A. K. The v-mos and c-Ha-ras oncoproteins exert similar effects on the pattern of protein synthesis. Oncogene 4, 799-803 (1989).
78. Rossler, U., Andres, A. C., Reichmann, E., Schmahl, W. & Werenskiold, A. K. T1, an immunoglobulin superfamily member, is expressed in H-ras-dependent epithelial tumours of mammary cells. Oncogene 8 609-617 (1993).
79. Oshikawa, K., Yanagisawa, K., Ohno, S., Tominaga, S. & Sugiyama, Y. Expression of ST2 in helper T lymphocytes of malignant pleural effusions. Am. J. Respir. Crit. Care Med. 165, 1005-1009 (2002).
80. Weinberg, E. O. et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106, 2961-2966 (2002).
81. Shimpo, M. et al. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 109, 2186-2190 (2004).
82. Daniels, L. B. & Maisel, A. S. Natriuretic peptides. J. Am. Coll. Cardiol. 50, 2357-2368 (2007).
83. Weinberg, E. O. et al. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 107 721-726 (2003).
84. Januzzi, J. L. Jr et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am. J. Cardiol. 95, 948-954 (2005).
85. Sabatine, M. S. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N. Engl. J. Med. 352, 1179-1189 (2005).
86. Morrow, D. A. et al. TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation 102, 2031-2037 (2000).
87. Amman, E. M. et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 284, 835-842 (2000).
88. Sabatine, M. S. et al. Complementary roles for biomarkers of biomechanical strain, ST2 and NT-proBNP, in patients with ST-elevation myocardial infarction. Circulation 117, 1936-1944 (2008).
89. Zethelius, B. et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N. Engl. J. Med. 358, 2107-2116 (2008).
90. Mallory, G., White, P. & Salcedo-Salgar, J. The speed of healing of myocardial infarction: A study of the pathologic anatomy in seventy-two cases. Am. Heart J. 18, 647-671 (1939).
91. Fishbein, M. C., Maclean, D. & Maroko, P. R. The histopathologic evolution of myocardial infarction. Chest 73, 843-849 (1978).
92. Frangogiannis, N. G., Smith, C. W. & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Res. 53, 31-47 (2002).
93. Hepper, N. G., Pruitt, R. D., Donald, D. E. & Edwards, J. E. The effect of cortisone on experimentally produced myocardial infarcts. Circulation 11, 742-748 (1955).
94. Johnson, A. S., Scheinberg, S. R., Gerisch, R. A. & Saltzstein, H. C. Effect of cortisone on the size of experimentally produced myocardial infarcts. Circulation 7, 224-228 (1953).
95. Libby, P., Maroko, P. R., Bloor, C. M., Sobel, B. E. & Braunwald, E. Reduction of experimental myocardial infarct size by corticosteroid administration. J. Clin. Invest. 52, 599-607 (1973).
96. Opdyke, D. F., Lambert, A., Stoerk, H. C., Zanetti, M. E. & Kuna, S. Failure to reduce the size of experimentally produced myocardial infarcts by cortisone treatment. Circulation 8, 544-548 (1953).
97. Roberts, R., DeMello, V. & Sobel, B. E. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 53, 1204-206 (1976).
98. Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121-1135 (2007).
99. + T lymphocytes. Circulation 114, 2056-2064 (2006).
100. Timmers, L. et al. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ. Res. 102, 257-264 (2008).
101. Diez, J., Gonzalez, A., Lopez, B. & Querejeta, R. Mechanisms of disease: pathologic structural remodeling is more than adaptive hypertrophy in hypertensive heart disease. Nature Clin. Pract. Cadiovasc. Med. 2, 209-216 (2005).
102. McKinsey, T. A. & Olson, E. N. Toward transcriptional therapies for the failing heart: Chemical screens to modulate genes. J. Clin. Invest. 115, 538-546 (2005).
103. Marian, A. J. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 355, 58-60 (2000).
104. Baudino, T. A., Carver, W., Giles, W. & Borg, T K. Cardiac fibroblasts: friend or foe? Am. J. Physiol. 291, H1015-1026 (2006).
105. Sadoshima, J. & Izumo, S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu. Rev. Physiol. 59, 551-571 (1997).
106. Manabe, I., Shindo, T & Nagai, R. Gene expression in fibroblasts and fibrosis: Involvement in cardiac hypertrophy. Circ. Res. 91, 1103-1113 (2002).
107. Dzau, V. J. & Re, R. Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation 89, 493-498 (1994).
108. Klug, D., Robert, V. & Swynghedauw, B. Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am. J. Cardiol. 71, 46A-54A (1993).
109. Pouleur, H. Role of neurohormones in ventricular adaptation and failure. Am. J. Cardiol. 73, 36C-39C (1994).
110. Weber, K. T. & Brilla, C. G. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83, 1849-1865 (1991).
111. Werenskiold, A. K. et al. Bone matrix deposition of T1, a homologue of interleukin 1 receptors. Cell Growth Differ. 6, 171-177 (1995).
112. Robertson, A. K. & Hansson, G. K. T cells in atherogenesis: For better or for worse? Arterioscier Thromb. Vasc. Biol. 26, 2421-2432 (2006).
113. Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685-1695 (2005).
114. Hansson, G. K. & Libby, P. The immune response in atherosclerosis: A double-edged sword. Nature Rev. Immunol. 6, 508-519 (2006).
115. Jonasson, L., Holm, J., Skalli, C., Bondjers, G. & Hansson, G. K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6, 131-138 (1986).
116. Hansson, G. K., Holm, J. & Jonasson, L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am. J. Pathol. 135, 169-175 (1989).
117. Stemme, S., Rymo, L. & Hansson, G. K. Polyclonal origin of T lymphocytes in human atherosclerotic plaques. Lab. Invest. 65, 654-660 (1991).
118. Liuzzo, G. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883-2888 (2000).
119. -/- mice. Decreasing density with disease progression. Arterioscier Thromb. Vasc. Biol. 16, 1013-1018 (1996).
120. +T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102, 2919-2922 (2000).
121. Reardon, C. A. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscier. Thromb. Vasc. Biol. 21, 1011-1016 (2001).
122. Song, L., Leung, C. & Schindler, C. Lymphocytes are important in early atherosclerosis. J. Clin. Invest. 108, 251-259 (2001).
123. Dansky, H. M., Charlton, S. A., Harper, M. M. & Smith, J. D. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc. Natl Acad. Sci. USA 94 4642-4646 (1997).
124. Glass, C. K. & Witztum, J. L. Atherosclerosis. the road ahead. Cell 104, 503-516 (2001).
125. Palinski, W. et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc. Natl Acad. Sci. USA 86, 1372-1376 (1989).
126. Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C. & Witztum, J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 320, 915-924 (1989).
127. Witztum, J. L. The oxidation hypothesis of atherosclerosis. Lancet 344, 793-795 (1994).
128. Nakajima, T. et al. De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. Circ. Res. 93, 106-113 (2003).
129. Tupin, E. et al. CD 1d-dependent activation of NKT cells aggravates atherosclerosis. J. Exp. Med. 199, 417-422 (2004).
130. Zhou, X., Robertson, A. K., Rudling, M., Parini, P. & Hansson, G. K. Lesion development and response to immunization reveal a complex role for CD4 in atherosclerosis. Circ. Res. 96, 427-434 (2005).
131. Frostegard, J. et al. Cytokine expression in advanced human atherosclerotic plaques: Dominance of proinflammatory (Th 1) and macrophage-stimulating cytokines. Atherosclerosis 145, 33-43 (1999).
132. Uyemura, K. et al. Cross-regulatory roles of interleukin (IL)- 12 and IL-10 in atherosclerosis. J. Clin. Invest. 97, 2130-2138 (1996).
133. 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. 19, 734-742 (1999).
134. Buono, C. et al. Influence of interferon-γ on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler. Thromb. Vasc. Biol. 23, 454-460 (2003).
135. Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752-2761 (1997).
136. -/- mice. Am. J. Pathol. 157, 1819-1824 (2000).
137. Mallat, Z. et al. Interleukin- 18/interleukin- 18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41-E45 (2001).
138. Buono, C. et al. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc. Natl Acad. Sci. USA 102, 1596-1601 (2005).
139. Mallat, Z. et al. Expression of interleukin- 18 in human atherosclerotic plaques and relation to plaque instability. Circulation 104, 1598-1603 (2001).
140. Huber, S. A., Sakkinen, R, David, C., Newell, M. K. & Tracy, R. P. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 103, 2610-2616 (2001).
141. Binder, C. J. et al. IL-S links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114, 427-437 (2004).
142. Davenport, P. & Tipping, P. G. The role of interleukin-4 and interleukin- 12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am. J. Pathol. 163, 1117-1125 (2003).
143. -/- mice. Arterioscler Thromb. Vasc. Biol. 22, 456-461 (2002).
144. Shimizu, K., Shichiri, M., Libby, P., Lee, R. T. & Mitchell, R. N. Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas. J. Clin. Invest. 114, 300-308 (2004).
145. Leskinen, M. J., Kovanen, P. T. & Lindstedt, K. A. Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells - a potential mechanism for the weakening and rupture of atherosclerotic plaques. Biochem. Pharmacol. 66, 1493-1498 (2003).
146. Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M. & Maeda, N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Natl Acad. Sci. USA 89, 4471-4475 (1992).
147. Plump, A. S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343-353 (1992).
148. Zhang, S. H., Reddick, R. L., Piedrahita, J. A. & Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468-471 (1992).
149. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092-1102 (2005).
150. Kerr, D. J. et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N. Engl. J. Med. 357 360-369 (2007).
151. Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes - an interim analysis. N. Engl. J. Med. 357, 28-38 (2007).
152. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457-2471 (2007).
153. Riad, A. et al. Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J. Immunol. 180, 6954-6961 (2008).
154. Ha, T et al. Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc. Res. 68, 224-234 (2005).
155. Hua, F. et al. Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J. Immunol. 178, 7317-7324 (2007).
156. Zhu, X. et al. My D88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. Am. J. Physiol. 291, H1900-H1909 (2006).
157. Boraschi, D. & Tagliabue, A. The interleukin-1 receptor family. Vitam. Horm. 74, 229-254 (2006).
158. Watters, T. M., Kenny, E. F. & O'Neill, L. A. Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol. Cell Biol. 85, 411-419 (2007).
159. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783-801 (2006).
160. Priestle, J. P., Schar, H. P. & Grutter, M. G. Crystallographic refinement of interleukin 1β at 2.0 Å resolution. Proc. Natl Acad. Sci. USA 86, 9667-9671 (1989).
161. Allan, S. M., Tyrrell, P. J. & Rothwell, N. J. Interleukin-1 and neuronal injury. Nature Rev. Immuno. 5, 629-640 (2005).
162. Nicklin, M. J. et al. A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 79, 718-725 (2002).
163. Taylor, S. L., Renshaw, B. R., Garka, K. E., Smith, D. E. & Sims, J. E. Genomic organization of the interleukin-1 locus. Genomics 79 726-733 (2002).
164. Dale, M. & Nicklin, M. J. Interleukin-1 receptor cluster: Gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q. Genomics 57, 177-179 (1999).
165. Farrar, J. D., Asnagli, H. & Murphy, K. M. T helper subset development: roles of instruction, selection, and transcription. J. Clin. Invest. 109, 431-435 (2002).
166. Smithgall, M. D. et al. IL-33 amplifies both Th1-and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int. Immunol. 11 June 2008 (doi: 10.1093/intimm/dxn060).
167. Cherry, W. B., Yoon, J., Bartemes, K. R., Iijima, K. & Kita, H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484-1490 (2008).
168. Palmer, G. et al. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine 42, 358-364 (2008).
169. Hill, J. A. & Olson, E. N. Cardiac plasticity. N. Engl. J. Med. 358, 1370-1380 (2008).
170. Grossman, W., Jones, D. & McLaurin, L. P. Wall stress and patterns of hypertrophy in the human left ventricle. J. Clin. Invest. 56 56-64 (1975).
171. Mann, D. L. & Bristow, M. R. Mechanisms and models in heart failure: The biomechanical model and beyond. Circulation 111, 2837-2849 (2005).
172. Frey, N. & Olson, E. N. Cardiac hypertrophy: The good, the bad, and the ugly. Annu. Rev. Physiol. 65, 45-79 (2003).
173. Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348 2007-2018 (2003).