Interleukin-33, a Novel Member of the IL-1/IL-18 Cytokine Family, in Cardiology and Cardiac Surgery

Abstract

Interleukin-33 is a newly recognized cytokine of the IL-1 family. Unlike its other members IL-1α, IL-1β and IL-18, interleukin-33 induces predominantly Th2-skewed immune responses. In this context, the effects of IL-33 are mostly anti-inflammatory. However, depending on the actual cytokine and cellular milieu, IL-33 can promote both Th1 and Th2 immune reactions. Most importantly for cardiology and cardiac surgery, IL-33 has emerged to represent the as yet unknown ligand of the orphan receptor ST2. Before the advent of IL-33, the ST2 receptor, currently recognized as the soluble one of its two isoforms, was considered to be an unfavorable prognostic marker in myocardial infarction, congestive heart failure and trauma/sepsis shock patients. Now we know that IL-33, when bound to the cellular membrane-anchored ST2L isoform of the receptor, can have certain beneficial effects on the aforementioned conditions. Various forms of IL-33 interaction with the respective isoforms of its cognate receptor are discussed here. The focus is on physiological and prognostic values in cardiac patients.

Key words

interleukin‐33 - soluble and membrane‐anchored ST2L receptor - angiogenesis - biomechanical strain - congestive heart failure - myocardial infarction

References

• 1 Arend W P, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines.  Immunol Rev. 2008;  223 20-38
• 2 Schmitz J, Owyang A, Oldham E 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. 2005;  23 479-490
• 3 Lohning M, Stroehmann A, Coyle A J 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. 1998;  95 6930-6935
• 4 Suzukawa M, Iikura M, Koketsu R et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor.  J Immunol. 2008;  181 5981-5989
• 5 Weinberg E O, Shimpo M, De Keulenaer G W et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction.  Circulation. 2002;  106 2961-2966
• 6 Baekkevold E S, Roussigne M, Yamanaka T et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules.  Am J Pathol. 2003;  163 69-79
• 7 Towne J E, Garka K E, Renshaw B R, Virca G D, Sims J E. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-κB and MAPKs.  J Biol Chem. 2004;  279 13677-13688
• 8 Chackerian A A, Oldham E R, Murphy E E, Schmitz J, Pflanz S, Kastelein R A. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex.  J Immunol. 2007;  179 2551-2555
• 9 Rehman S U, Mueller T, Januzzi Jr J L. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure.  J Am Coll Cardiol. 2008;  52 1458-1465
• 10 Bartunek J, Delrue L, Van Durme F et al. Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load.  J Am Coll Cardiol. 2008;  52 2166-2174
• 11 Januzzi Jr J L, Peacock W F, Maisel A S 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. 2007;  50 607-613
• 12 Sanada S, Hakuno D, Higgins L J, Schreiter E R, McKenzie A N J, Lee R T. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system.  J Clin Invest. 2007;  117 1538-1549
• 13 Aoki A, Hayakawa M, Ozaki H et al. ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells.  Mol Cell Biochem. 2010;  335 75-81
• 14 Heerdt P M, Holmes J W, Cai B et al. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alteres gene expression in end-stage heart failure.  Circulation. 2000;  102 2713-2719
• 15 Sabatine M S, Morrow D A, Higgins L J et al. Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction.  Circulation. 2008;  117 1936-1944
• 16 Weinberg E O, Shimpo M, De Keulenaer G W et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction.  Circulation. 2002;  106 2961-2966
• 17 Mega J L, Morrow D A, De Lemos J A et al. B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction: an ENTIRE-TIMI-23 substudy.  J Am Coll Cardiol. 2004;  44 335-339
• 18 Pascual-Figal D A, Ordonez-Llanos J, Tornel P L et al. Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction.  J Am Coll Cardiol. 2009;  54 2174-2179
• 19 Weinberg E O, Shimpo M, Hurwitz S, Tominaga S, Rouleau J L, Lee R T. Identification of serum soluble ST2 receptor as a novel heart failure biomarker.  Circulation. 2003;  107 721-726
• 20 Seki K, Sanada S, Kudinova A Y et al. Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling.  Circ Heart Fail. 2009;  2 684-691
• 21 Brunner M, Krenn C, Roth G et al. Increased levels of soluble ST2 protein and IGg1 production in patients with sepsis and trauma.  Intensive Care Med. 2004;  30 1468-1473
• 22 Osuchowski M F, Welch K, Siddiqui J, Remick D G. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality.  J Immunol. 2006;  177 1967-1974
• 23 Fagundes C T, Amaral F A, Souza A L S et al. ST2, an IL-1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion.  J Leukocyte Biol. 2007;  81 492-499
• 24 Yin H, Huang B-J, Yang H et al. Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury.  Biochem Biophys Res Commun. 2006;  351 940-946
• 25 Liew F Y, Liu H, Xu D. A novel negative regulator for IL-1 receptor and Toll-like receptor 4.  Immunol Lett. 2005;  96 27-31
• 26 Liew F Y, Pitman N I, McInnes I B. Disease-associated functions of IL-33: the new kid in the IL-1 family.  Nat Rev Immunology. 2010;  10 103-110
• 27 Takezako N, Hayakawa M, Hayakawa H et al. ST2 suppresses IL-6 production via the inhibition of IκB degradation induced by the LPS signal in THP-1 cells.  Biochem Biophys Res Commun. 2006;  341 425-432
• 28 Brint E K, Xu D, Liu H et al. ST2 is an inhibitor of interleukin-1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance.  Nat Immunol. 2004;  5 373-379
• 29 Pushparaj P N, Tay H K, H'ng S C et al. The cytokine interleukin-33 mediates anaphylactic shock.  Proc Natl Acad Sci USA. 2009;  106 9773-9778
• 30 Smithgall M D, Comeau M R, Yoon Park B-R, Kaufman D, Armitage R, Smith D E. 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. 2008;  20 1019-1030
• 31 Carriere V, Roussel L, Ortega N 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. 2007;  104 282-287
• 32 Werman A, Werman-Venkert R, White R et al. The precursor form of IL-1α is an intracrine proinflammatory activator of transcription.  Proc Natl Acad Sci USA. 2004;  101 2434-2439
• 33 Scaffidi P, Misteli T, Bianchi M E. Release of chromation protein HMGB1 by necrotic cells triggers inflammation.  Nature. 2002;  418 191-195
• 34 Bonaldi T, Talamo F, Scaffidi P et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion.  EMBO J. 2003;  22 5551-5560
• 35 Murphy G E J, Xu D, Liew F Y, McInnes I B. Role of interleukin-33 in human immunopathology.  Ann Rheum Dis. 2010;  69 i43-i47
• 36 Haraldsen G, Balogh J, Pollheimer J, Sponheim J, Küchler A M. Interleukin-33 – cytokine of dual function or novel alarmin?.  Trends Immunol. 2009;  30 227-233
• 37 Küchler A M, Pollheimer J, Balogh J et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation.  Am J Pathol. 2008;  173 1229-1242
• 38 Möhle R, Green D, Moore M A, Nachman R L, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets.  Proc Natl Acad Sci USA. 1997;  94 663-668
• 39 Syed F M, Hahn H S, Odley A et al. Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia.  Circ Res. 2005;  96 1103-1109
• 40 Szerafin T, Niederpold T, Mangold A et al. Secretion of soluble ST2 – possible explanation for systemic immunosuppression after heart surgery.  Thorac Cardiovasc Surg. 2009;  57 25-29
• 41 Sämpi M, Ukkola O, Päivänsalo M, Antero Kesäniemi Y, Binder C J, Hörkkö S. Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis.  J Am Coll Cardiol. 2008;  52 1370-1378
• 42 Kuhn E, Addona T, Keshishian H et al. Developing multiplexed assays for troponin I and interleukin-33 in plasma by peptide immunoaffinity enrichment and targeted mass spectrometry.  Clin Chem. 2009;  55 1108-1117

Addendum

Since ST2/IL33 is an extraordinarily vast topic which extends into virtually all fields of contemporary medicine, ours is only a modest contribution designed to offer a basic up-to-date overview to the cardiac surgeon who, as we know from our own experience, is an extremely busy man or woman. This theme may be promising for the future, just as it may prove to be a blind alley. Personally, we believe the former. Due to the constraints of time and space, we were not able to treat the topic in full length or to exploit all the available relevant literature. For the interested reader, we have included some of the latest reviews and papers of extraordinary quality. Other papers will undoubtedly follow. Whether they will be directed predominantly at immunologists or also at cardiologists/cardiac surgeons is hard to tell. Owing to the fact that immunology and molecular biology affect all medical fields, we hope that the time spent in reading this article will not be “le temps perdu”.

Additional Reading

• 43 Schmidt D R, Kao W J. The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function.  Biomaterials. 2007;  28 371-382
• 44 Miller A M, Xu D, Asquith D L et al. IL-33 reduces the development of atherosclerosis.  J Exp Med. 2008;  205 339-346
• 45 Wood I S, Wang B, Trayhurn P. IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes.  Biochem Biophys Res Commun. 2009;  384 105-109
• 46 Weinberg E O. ST2 protein in heart disease: from discovery to mechanisms and prognostic value.  Biomarkers Med. 2009;  3 495-511
• 48 Weir R A P, Miller A M, Murphy G E J et al. Serum soluble ST2. A potential novel mediator in left ventricular and infarct remodeling after acute myocardial infarction.  J Am Coll Cardiol. 2010;  55 243-250
• 49 Yin H, Li X-Y, Jin X-B et al. IL-33 prolongs murine cardiac allograft survival through induction of Th2-type immune deviation.  Transplantation. 2010;  89 1189-1197
• 50 Shah R V, Januzzi Jr J L. ST2: a novel remodeling biomarker in acute and chronic heart failure.  Curr Heart Fail Rep. 2010;  7 9-14
• 51 Kakkar R, Lee R T. Intramyocardial fibroblast myocyte communication.  Circ Res. 2010;  106 45-57