Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Drug Discovery volume 7, pages 827–840 (2008)Cite this article

Key Points

  • Interleukin-33 (IL-33) is a recently discovered member of the IL-1 family of cytokines.

  • The receptor for IL-33, ST2, is present in multiple isoforms, including a membrane-bound form (ST2L), which together with the interleukin-1 (IL-1) receptor accessory protein forms the transmembrane IL-33 receptor, and a soluble form (sST2), which may act as a decoy receptor for IL-33.

  • ST2L was originally investigated as a cell-surface marker for a subclass of T-cell leukocytes, the type II T-helper (Th2) cell. More recently, ST2L has been shown to participate in activation of antigen-primed Th2 cells.

  • ST2 has been implicated in numerous inflammatory conditions such as asthma, fibroproliferative diseases, autoimmune diseases, including rheumatoid arthritis, and septic shock.

  • The intracellular signalling cascade of IL-33 might share many of the features of canonical Toll-like receptor/IL-1-receptor superfamily signalling. Furthermore, IL-33 may also exhibit direct nuclear targeting.

  • Soluble ST2 has emerged as a novel cardiac biomarker. Elevated serum sST2 levels identify heart failure or myocardial infarction patients with higher mortality. As a potential diagnostic assay, elevated serum sST2 levels identify high-risk patients presenting with shortness of breath.

  • The IL-33/ST2 system appears to participate in cardiac protection. IL-33 produced by fibroblasts may dampen the maladaptive pro-hypertrophic and pro-fibrotic response of the myocardium to biomechanical overload.

  • IL-33 might also be protective against atherosclerosis. Administration of IL-33 to mice that are prone to atherosclerotic vascular disease can abrogate plaque build-up in the vessel wall.

  • Although the IL-33/ST2L signalling cascade may provide targets for therapeutic intervention, consideration must be given to its apparent diverse roles.

Abstract

For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine — interleukin-33 (IL-33) — was identified as a functional ligand for ST2. IL-33/ST2 signalling is involved in T-cell mediated immune responses, but more recently, an unanticipated role in cardiovascular disease has been demonstrated. IL-33/ST2 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast–cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A model for IL-33/ST2 signalling.
Figure 2: IL-33 in the type 2 immune response.
Figure 3: IL-33/ST2 signalling is a novel cardioprotective fibroblast–cardiomyocyte paracrine system.
Figure 4: IL-33/ST2 reduces atheroma formation.
Figure 5: Strategies and consequences of IL-33/ST2 modulation.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Sims, J. E. IL-1 and IL-18 receptors, and their extended family. Curr. Opin. Immunol. 14, 117–122 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  4. Meisel, C. et al. Regulation and function of T1/ST2 expression on CD4+ T cells: induction of type 2 cytokine production by T1/ST2 cross-linking. J. Immunol. 166, 3143–3150 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This study identifies IL-33 as the functional ligand of ST2L, documenting the production of Th2-related cytokines both in vitro and in vivo.

    Article  CAS  PubMed  Google Scholar 

  11. Dinarello, C. A. An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity 23, 461–462 (2005).

    Article  CAS  PubMed  Google Scholar 

  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). This was the first study to suggest that IL-33 might act as a fibroblast–cardiomyocyte signalling system. IL-33 was found to be upregulated in fibroblasts when they were subjected to biomechanical strain and to modulate cardiomyocyte NF-κB levels, resulting in resistance to the effects of cardiac pressure overload injury in the in vivo model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miller, A. M. et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205, 339–346 (2008). This study documents the anti-atherosclerotic effect of exogenous IL-33 administration in the ApoE -null mouse, a model of accelerated atherogenesis. This effect is suggested to be mediated through a shift from a Th1 to a Th2 immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This study builds upon previous data regarding sST2 as a cardiac biomarker, suggesting that serum levels of sST2 might be sensitive enough to distinguish between cardiovascular and non-cardiovascular causes of shortness of breath in patients presenting to the emergency ward.

    Article  CAS  PubMed  Google Scholar 

  15. Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  17. Abreu, M. T. & Arditi, M. Innate immunity and toll-like receptors: clinical implications of basic science research. J. Pediatr. 144, 421–429 (2004).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  22. Takagi, T. et al. Identification of the product of the murine ST2 gene. Biochim. Biophys. Acta 1178, 194–200 (1993).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This study documents the intranuclear properties of IL-33. IL-33 was found to be heterochromatin-associated in human endothelial cells, exerting a repressive effect on DNA transcription. The authors identify a conserved N-terminal motif that is necessary and sufficient for targeting IL-33 to the nucleus.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  40. Gadina, M. & Jefferies, C. A. IL-33: a sheep in wolf's clothing? Sci. STKE 390, pe31 (2007).

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  42. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This study characterizes the IL-33 receptor as ST2L and the IL-1R accessory protein (IL-1RAcP).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Funakoshi-Tago, M. et al. TRAF6 is a critical signal transducer in IL-33 signaling pathway. Cell. Signal. 20, 1679–1686 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). This study suggests that ST2L negatively regulates TLR-4 signalling by sequestering the adaptor proteins MAL and MyD88. Furthermore, ST2 -null mice did not develop tolerance to repeated LPS exposure.

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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). The anti-IL-33 effects of sST2 are clarified in this study. Specifically, sST2 is shown to bind IL-33 and suppress activation of NF-κB, as well as abrogate the expression of Th2-associated cytokines.

    Article  CAS  PubMed  Google Scholar 

  52. Komai-Koma, M. et al. IL-33 is a chemoattractant for human Th2 cells. Eur. J. Immunol. 37, 2779–2786 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  54. Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245–248 (1993).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kropf, P. et al. Identification of two distinct subpopulations of Leishmania major-specific T helper 2 cells. Infect. Immun. 70, 5512–5520 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ying, S. et al. Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 158, 3539–3544 (1997).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  63. Moulin, D. et al. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 40, 216–225 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Oshikawa, K. et al. Acute eosinophilic pneumonia with increased soluble ST2 in serum and bronchoalveolar lavage fluid. Respir. Med. 95, 532–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Wynn, T. A. Fibrotic disease and the TH1/TH2 paradigm. Nature Rev. Immunol. 4, 583–594 (2004).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  68. Amatucci, A. et al. Recombinant ST2 boosts hepatic Th2 response in vivo. J. Leukoc. Biol. 82, 124–132 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  70. Wynn, T. A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117, 524–529 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). This study establishes sST2 as a cardiac biomarker, documenting a correlation between sST2 levels in patients presenting to hospital with myocardial infarction and the chance of death or of developing heart failure.

    Article  CAS  PubMed  Google Scholar 

  82. Daniels, L. B. & Maisel, A. S. Natriuretic peptides. J. Am. Coll. Cardiol. 50, 2357–2368 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Weinberg, E. O. et al. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 107, 721–726 (2003).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  87. Antman, 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  91. Fishbein, M. C., Maclean, D. & Maroko, P. R. The histopathologic evolution of myocardial infarction. Chest 73, 843–849 (1978).

    Article  CAS  PubMed  Google Scholar 

  92. Frangogiannis, N. G., Smith, C. W. & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovascular Res. 53, 31–47 (2002).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  97. Roberts, R., DeMello, V. & Sobel, B. E. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 53, I204–206 (1976).

    Article  CAS  PubMed  Google Scholar 

  98. Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121–1135 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Yang, Z. et al. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114, 2056–2064 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Marian, A. J. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 355, 58–60 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Baudino, T. A., Carver, W., Giles, W. & Borg, T. K. Cardiac fibroblasts: friend or foe? Am. J. Physiol. 291, H1015–1026 (2006).

    CAS  Google Scholar 

  105. Sadoshima, J. & Izumo, S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu. Rev. Physiol. 59, 551–571 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Manabe, I., Shindo, T. & Nagai, R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy. Circ. Res. 91, 1103–1113 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Dzau, V. J. & Re, R. Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation 89, 493–498 (1994).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  109. Pouleur, H. Role of neurohormones in ventricular adaptation and failure. Am. J. Cardiol. 73, 36C–39C (1994).

    Article  CAS  PubMed  Google Scholar 

  110. Weber, K. T. & Brilla, C. G. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin–angiotensin–aldosterone system. Circulation 83, 1849–1865 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Werenskiold, A. K. et al. Bone matrix deposition of T1, a homologue of interleukin 1 receptors. Cell Growth Differ. 6, 171–177 (1995).

    CAS  PubMed  Google Scholar 

  112. Robertson, A. K. & Hansson, G. K. T cells in atherogenesis: for better or for worse? Arterioscler. Thromb. Vasc. Biol. 26, 2421–2432 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Hansson, G. K. & Libby, P. The immune response in atherosclerosis: a double-edged sword. Nature Rev. Immunol. 6, 508–519 (2006).

    Article  CAS  Google Scholar 

  115. Jonasson, L., Holm, J., Skalli, O., 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Stemme, S., Rymo, L. & Hansson, G. K. Polyclonal origin of T lymphocytes in human atherosclerotic plaques. Lab. Invest. 65, 654–660 (1991).

    CAS  PubMed  Google Scholar 

  118. Liuzzo, G. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Roselaar, S. E., Kakkanathu, P. X. & Daugherty, A. Lymphocyte populations in atherosclerotic lesions of apoE−/− and LDL receptor−/− mice. Decreasing density with disease progression. Arterioscler. Thromb. Vasc. Biol. 16, 1013–1018 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Zhou, X., Nicoletti, A., Elhage, R. & Hansson, G. K. Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102, 2919–2922 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Reardon, C. A. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 1011–1016 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Song, L., Leung, C. & Schindler, C. Lymphocytes are important in early atherosclerosis. J. Clin. Invest. 108, 251–259 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Glass, C. K. & Witztum, J. L. Atherosclerosis. the road ahead. Cell 104, 503–516 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Palinski, W. et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc. Natl Acad. Sci. USA 86, 1372–1376 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  127. Witztum, J. L. The oxidation hypothesis of atherosclerosis. Lancet 344, 793–795 (1994).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  129. Tupin, E. et al. CD1d-dependent activation of NKT cells aggravates atherosclerosis. J. Exp. Med. 199, 417–422 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  131. Frostegard, J. et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145, 33–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Uyemura, K. et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J. Clin. Invest. 97, 2130–2138 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  135. Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mallat, Z. et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41–E45 (2001).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mallat, Z. et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 104, 1598–1603 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. 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 103, 2610–2616 (2001).

    Article  CAS  PubMed  Google Scholar 

  141. Binder, C. J. et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114, 427–437 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. King, V. L., Szilvassy, S. J. & Daugherty, A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor−/− mice. Arterioscler. Thromb. Vasc. Biol. 22, 456–461 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  151. Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes — an interim analysis. N. Engl. J. Med. 357, 28–38 (2007).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  154. Ha, T. et al. Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc. Res. 68, 224–234 (2005).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  156. Zhu, X. et al. MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. Am. J. Physiol. 291, H1900–H1909 (2006).

    CAS  Google Scholar 

  157. Boraschi, D. & Tagliabue, A. The interleukin-1 receptor family. Vitam. Horm. 74, 229–254 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  159. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Allan, S. M., Tyrrell, P. J. & Rothwell, N. J. Interleukin-1 and neuronal injury. Nature Rev. Immuno. 5, 629–640 (2005).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  169. Hill, J. A. & Olson, E. N. Cardiac plasticity. N. Engl. J. Med. 358, 1370–1380 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mann, D. L. & Bristow, M. R. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111, 2837–2849 (2005).

    Article  PubMed  Google Scholar 

  172. Frey, N. & Olson, E. N. Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Physiol. 65, 45–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  173. Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the reviewers for their invaluable advice.

Author information

Authors and Affiliations

  1. Division of Cardiology, GRB-804, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachussetts, USA

    Rahul Kakkar

  2. Brigham and Women's Hospital, Harvard Medical School, Partners Research Facility, Room 279 65 Landsdowne Street, Cambridge, 02139, Massachusetts, USA

    Richard T. Lee

Authors
  1. Rahul Kakkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard T. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Brigham and Women's Hospital has filed for patents on IL-33 and ST2, with Dr. Lee listed as an inventor.

Related links

Related links

DATABASES

OMIM

asthma

progressive systemic sclerosis

rheumatoid arthritis

systemic lupus erythematosis

Wegener's granulomatosis

FURTHER INFORMATION

Rahul Kakkar's homepage

Glossary

Th2 cells

A subset of the T-cell pool hypothesized to drive an immune response that is characterized by production of interleukin-4, -5,-6 and -10 (among others) in response to extracellular pathogens.

Cytokines

Small proteins released by cells of the immune system for the purpose of intercellular crosstalk. Interleukins, derived specifically from leukocytes, are a subset of these proteins.

Th1 cells

A subset of the T-cell pool hypothesized to drive an immune response that is characterized by the production of interleukin-2 and interferon-γ (among others) in response to intracellular pathogens.

Fibrosis

Process by which normal tissue is replaced with scar tissue, mostly consisting of extracellular proteins produced by fibroblasts.

Atherosclerotic vascular disease

A disease that is pathologically defined by the formation of lipid-rich lesions within the artery wall and which results in luminal narrowing and loss of vascular elasticity. It is characterized by a significant T-cell and macrophage inflammatory response to oxidized low-density lipoprotein.

The Toll-like/IL-1-receptor superfamily

A superfamily of related cytokine receptors. They are similar in that they contain a common intracellular domain, the Toll/Interleukin-1 receptor (TIR) domain.

Expressed Sequence Tag

(EST). Short, unique sequence of DNA that can be used to identify the larger gene transcript of which it is a part of. It is created by sequencing mRNA that represents a portion of the expressed sequence of a gene. ESTs have been used extensively to identify new genes within the genome.

High endothelial venules

Post-capillary tissue involved in leukocyte extravasation from lymphoid tissue.

Autocrine, paracrine and endocrine

Describe the type of interaction between a cell, its secreted compound and the affected target cell. Autocrine effects are those in which the effector cell is of the same type as the target cell. Paracrine effects are those in which the secreted protein exerts its effect on cells within the local vicinity of the effector cell. Endocrine effects are those which occur at a distance (the effector cell secretes its proteins into the blood stream).

Angiotensin II

A protein that circulates in the bloodstream and exerts a myriad of physiological effects. Effects of angiotensin II include arterial vasoconstriction, renal blood filtration and sodium absorption, cardiac myocyte hypertrophy and ventricular fibrosis, platelet aggregation, adrenal aldosterone secretion and increased thirst sensation in the brain.

Cardiomyocytes

Specialized, striated muscle cells of the heart. These cells are contiguous with one another, allowing the rapid transmission of chemical and electrical signals between them. An extracellular matrix of proteins, secreted by resident fibroblasts, serves to both mechanically bind them and transduce information about the extracellular environment.

Decoy receptors

Proteins that can bind the ligand of functional cellular receptors, effectively reducing the concentration of ligand that is available to the active receptor.

Antigen

Substance which can induce an immune response. Generally it is a fragment of a protein or polysaccharide that is derived from a structural component of a pathogen, such as a component of the bacterial cell wall.

Sepsis

A pattern of body-wide responses to overwhelming infection. It is characterized by alteration in core body temperature, vasodilation with attendant drop in blood pressure and rise in heart rate, and leukocyte response. These responses are thought to be mediated by the release of inflammatory cytokines.

Endotoxin

A lipopolysaccaride within the gram-negative bacterial cell wall that upon infection may instigate sepsis, septic shock and its associated complications.

Myocardial infarction

Term used to describe the death of heart tissue due to a loss of blood supply.

STEMI

Term used to describe the most severe type of heart attack. Defined by elevation of the 'ST-segment' on the standard electrocardiogram, this entity is typified by complete occlusion of a coronary artery and subsequent death of downstream cardiac tissue.

The Killip classification

A risk stratification system developed by Killip and colleagues in 1967 after a two-year observation of an unselected group of 250 patients presenting to hospital with myocardial infarction. It employs physical exam findings consistent with heart failure or cardiogenic shock to categorize patients into one of four classes. The class assigned correlates with mortality at 30 days after the infarction.

Brain natriuretic peptide (BNP).

Protein that is released from ventricular myocardial cells under stress or strain. It is cleaved from its precursor pro-BNP along with N-terminal-pro-BNP. Its biological effects include systemic vasoconstriction and renal sodium loss.

Odds ratio

Ratio of the odds of an outcome among exposed individuals compared with the odds of the outcome among unexposed individuals.

C statistic

A quantitative measure of the ability of a test to discriminate between two cohorts, typically those with and without a disease. The C statistic varies between 0.5 and 1.0, with a higher value denoting better discriminatory power. For binary outcomes, C is identical to the area under the receiver operating characteristic (ROC) curve, or a plot of sensitivity (SN) versus one minus specificity (1-SP) of the test in question.

Antigen-presenting cell

Cell which processes and presents antigen on its cell surface to effector immune cells, for example, T-cells. The antigen is displayed within a specialized protein receptor, known as the major histocompatibility complex, along with other co-receptors that are necessary for effector immune cell activation.

Apolipoprotein E

(ApoE). A protein component of some lipoproteins. Lipoproteins are conglomerates of proteins and lipids that serve to shuttle fat and cholesterol through the bloodstream. ApoE allows its lipoproteins to be taken up by the liver as part of the normal process of lipid clearance from the blood. ApoE-null mice have high blood levels of cholesterol and display spontaneous atherosclerosis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kakkar, R., Lee, R. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 7, 827–840 (2008). https://doi.org/10.1038/nrd2660

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2660

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing