S.T. Matskeplishvili – Dr.Sc. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences,

Director for Research, Medical Research and Education Center of Lomonosov Moscow State University

E.I. Rumiantseva – 5th-year Student, Faculty of Fundamental Medicine, Lomonosov Moscow State University  E-mail: lizarum17@yandex.ru

O.A. Tsatsulina – 5th-year Student, Faculty of Fundamental Medicine, Lomonosov Moscow State University  E-mail: Olga.Tsatsulina@gmail.com

Signaling cascade IL-33/ST2 is important in different processes. In this review we analyze molecular aspects of this cascade and its role in oncology, immunopathology and cardiology. ST2 is a protein of the interleukin-1 family. The most significant are two isoforms of ST2: ST2L – a membrane-anchored receptor for interleukin-33 (IL-33), and sST2 – soluble isoform, which is able to bind to IL-33 and reduce its level in the blood. The amount and activity of IL-33 is regulated at several levels by various mechanisms: at the stages of transcription and post-transcription, by caspases 3 and 7 and by binding to sST2, etc. IL-33 promotes differentiation of T-cells into Th2 type and macrophages into the M2 type responsible for anti-inflammatory processes and repair. These immune effects are important in pathogenesis of atopic dermatitis, asthma, atherosclerosis. IL33/ST2 cascade is significant in cancer pathophysiology: ST2 and IL-33 mRNA is detected in the stroma of pulmonary, gastric, renal cell and hepatocellular carcinoma. According to various studies, IL-33 can be regarded as an antitumor factor, and

IL-33/ST2 cascadeas is a protumor factor. IL-33/ST2 cascade is the most intensively studied in cardiology. In a normal heart, IL-33, produced by fibroblasts, binds to ST2L and triggers a cascade that results in increased NF-kB activity and protection from hypertrophy and fibrosis. In the case of heart failure, sST2, which is released in large quantities, acts as a decoyreceptor for IL-33, disrupts ST2L binding, thus reducing cardioprotective effects, increases inflammation, stretching of cardiomyocytes and fibrosis. A large number of randomized trials have shown that ST2 is a promising marker for the prognosis, staging and monitoring of heart failure. One of the largest studies – TRIUMPH has shown that sST2 level and its dynamics correlate with mortality and prognosis in chronic heart failure. The IL-33/ST2 axis is also important in the progression of atherosclerosis. It is proved that IL-33 in mice reduces the number and size of atherosclerotic plaques, and the level of ST2 correlates with pulse pressure in the aorta in patients with hypertension. Further study of the role of sST2 in the pathogenesis of cardiovascular diseases and cancer, as well as patterns of changes in its concentration in the blood in these pathologies can expand the possibilities of prognosing and staging many common pathological conditions and diseases, including chronic heart failure.

1. Yancy C.W., Jessup M., Bozkurt B. et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology / American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of Amer // J. Am. Coll. Cardiol. 2017. V. 70. № 6. P. 776–803.
2. la Fuente M. Da, MacDonald T.T., Hermoso M.A. The IL-33/ST2 axis: Role in health and disease // Cytokine Growth Factor Rev. 2015. V. 26. № 6. P. 615–623.
3. 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. 1989. P. 301–304.
4. Yanagisawa K., Takagi T., Tsukamoto T. et al. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1 // FEBS Lett. 1993. V. 318. № 1. P. 83–87.
5. Griesenauer B., Paczesny S. The ST2/IL-33 axis in immune cells during inflammatory diseases // Front. Immunol. 2017.  V. 8. P. 1–17.
6. Lu J., Kang J., Zhang C. et al. The role of IL-33/ST2L signals in the immune cells // Immunol. Lett. 2015. V. 164. № 1. P. 11–17.
7. Vark L.C. van, Lesman-Leegte I., Baart S.J. et al. Prognostic Value of Serial ST2 Measurements in Patients With Acute Heart Failure // J. Am. Coll. Cardiol. 2017. V. 70. № 19. P. 2378–2388.
8. Iwahana H., Hayakawa M., Kuroiwa K. et al. Molecular cloning of the chicken ST2 gene and a novel variant form of the ST2 gene product, ST2LV // Biochim. Biophys. Acta – Gene Struct. Expr. 2004. V. 1681. № 1. P. 1–14.
9. Cayrol C., Girard J.P. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family // Immunol. Rev. 2018. V. 281. № 1. P. 154–168.
10. Lott J.M., Sumpter T.L., Turnquist H.R. New dog and new tricks: evolving roles for IL-33 in type 2 immunity // J. Leukoc. Biol. 2015. V. 97. № 6. P. 1037–1048.
11. Sun Z., Chang B., Gao M. et al. IL-33-ST2 Axis in Liver Disease: Progression and Challenge // Mediators Inflamm. 2017. V. 2017. P. 1–8.
12. Palmer G., Lipsky B.P., Smithgall M.D. 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. 2008. V. 42. № 3. P. 358–364.
13. Lu B., Yang M., Wang Q. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy // J. Mol. Med. 2016. V. 94. № 5. P. 535–543.
14. Jensen L.E., Whitehead A.S. Expression of alternatively spliced interleukin-1 receptor accessory protein mRNAs is differentially regulated during inflammation and apoptosis. // Cell. Signal. 2003. V. 15. № 8. P. 793–802.
15. Aimo A., Migliorini P., Vergaro G. et al. The IL-33/ST2 pathway, inflammation and atherosclerosis: Trigger and target? // Int. J. Cardiol. 2018. V. 267. P. 1–16.
16. Wang E., Jia X., Ruan C. et al. miR-487b mitigates chronic heart failure through inhibition of the IL-33 / ST2 signaling pathway // Oncotarget. 2017. V. 8. № 31. P. 51688–51702.
17. Pascual-Figal D.A., Januzzi J.L. The biology of ST2: The international ST2 consensus panel // Am. J. Cardiol. 2015.  V. 115. № 7. P. 3B–7B.
18. Gao Q., Li Y., Li M. The potential role of IL-33/ST2 signaling in fibrotic diseases // J. Leukoc. Biol. 2015. V. 98. № 1. P. 15–22.
19. Lefrançais E., Roga S., Gautier V. et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. // Proc. Natl. Acad. Sci. U. S. A. 2012. V. 109. № 5. P. 1673–8.
20. Romagnani S. T-cell subsets (Th1 versus Th2) // Ann. Allergy, Asthma Immunol. 2000. V. 85. № 1. P. 9–21.
21. Liew F.Y., Girard J.P., Turnquist H.R. Interleukin-33 in health and disease // Nat. Rev. Immunol. 2016. V. 16. № 11. P. 676–689.
22. Barlow J.L., Peel S., Fox J. et al. IL-33 is more potent than IL-25 in provoking IL-13–producing nuocytes (type 2 innate lymphoid cells) and airway contraction // J. Allergy Clin. Immunol. 2013. V. 132. № 4. P. 933–941.
23. Colin S., Chinetti-Gbaguidi G., Staels B. Macrophage phenotypes in atherosclerosis // Immunol. Rev. 2014. V. 262. № 1. P. 153–166.
24. Paoli F. De, Staels B., Chinetti-Gbaguidi G. Macrophage Phenotypes and Their Modulation in Atherosclerosis // Circ. J. 2014. V. 78. № 8. P. 1775–1781.
25. Xu D., Chan W.L., Leung B.P. et al. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells // J. Exp. Med. 1998. V. 187. № 5. P. 787–94.
26. Oh J., Riek A.E., Weng S. et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation // J. Biol. Chem. 2012. V. 287. № 15. P. 11629–41.
27. Su Z., Lin J., Lu F. et al. Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation // Mucosal Immunol. 2013. V. 6. № 5. P. 921–30.
28. Tjota M.Y., Williams J.W., Lu T. et al. IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling //  J. Clin. Invest. 2013. V. 123. № 5. P. 2287–97.
29. Cao K., Liao X., Lu J. et al. IL-33 / ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulation. 2018. V. 15. P. 1–12.
30. Khaitov M.R., Gaisina A.R., Shilovskiy I.P. et al. The Role of Interleukin 33 in Pathogenesis of Bronchial Asthma . New Experimental Data // Biochem. 2018. V. 83. № 1. P. 13–25.
31. Miller A.M., Liew F.Y. The IL-33/ST2 pathway – A new therapeutic target in cardiovascular disease // Pharmacol. Ther. 2011. V. 131. № 2. P. 179–186.
32. Milovanovic M., Volarevic V., Radosavljevic G. et al. IL-33/ST2 axis in inflammation and immunopathology // Immunol. Res. 2012. V. 52. № 1–2. P. 89–99.
33. Zhou Y., Ji Y., Wang H. et al. IL-33 Promotes the Development of Colorectal Cancer Through Inducing Tumor-Infiltrating ST2L + Regulatory T Cells in Mice // Technol. Cancer Res. Treat. 2018. V. 17. P. 1–11.
34. Yang Z., Gao X., Wang J. et al. Interleukin-33 enhanced the migration and invasiveness of human lung cancer cells // Onco. Targets. Ther. 2018. V. 11. P. 843–849.
35. Yang M., Feng Y., Yue C. et al. Lower expression level of IL-33 is associated with poor prognosis of pulmonary adenocarcinoma // PLoS One. 2018. V. 13. № 3. P. 1–13.
36. Wu C., Wu Y., Cheng C. et al. Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway // Cell. Physiol. Biochem. 2018. V. 47. № 1. P. 191–200.
37. Pawel S., Maciej M., Maciej Z. et al. Novel interleukin-33 and its soluble ST2 receptor as potential serum biomarkers in parotid gland tumors // Exp. Biol. Med. 2018. V. 243. № 9. P. 762–769.
38. Xu L., Li W., Wang X. et al. The IL-33-ST2-MyD88 axis promotes regulatory T cell proliferation in the murine liver // Eur. J. Immunol. 2018. V. 48. P. 1–18.
39. Bayés-Genís A., Núñez J., Lupón J. Soluble ST2 for Prognosis and Monitoring in Heart Failure // J. Am. Coll. Cardiol. 2017. V. 70. № 19. P. 2389–2392.
40. Altara R., Ghali R., Mallat Z. et al. Conflicting Vascular and Metabolic Impact of the IL-33 / sST2 Axis // 2018. 
41. Sanada S., Hakuno D., Higgins L.J. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system // J. Clin. Invest. 2007. V. 117. № 6. P. 1538–1549.
42. Aimo A., Vergaro G., Ripoli A. et al. Meta-Analysis of Soluble Suppression of Tumorigenicity-2 and Prognosis in Acute Heart Failure // JACC Hear. Fail. 2017. V. 5. № 4. P. 287–296.
43. Aimo A., Vergaro G., Passino C. et al. Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure: A Meta-Analysis // JACC. Heart Fail. 2017. V. 5. № 4. P. 280–286.
44. Pascual-Figal D.A., Ordoñez-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. V. 54. № 23. P. 2174–9.
45. Lupón J., Gaggin H.K., Antonio M. de et al. Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2R2 score // Int. J. Cardiol. 2015. V. 184. P. 337–43.
46. Bayes-Genis A., Pascual-Figal D., Januzzi J.L. et al. Soluble ST2 Monitoring Provides Additional Risk Stratification for Outpatients With Decompensated Heart Failure // Rev. Española Cardiol. (English Ed. 2010. V. 63. № 10. P. 1171–1178.
47. Bouwens E., Brankovic M., Mouthaan H. Temporal patterns of 7 blood biomarkers of cardiac remodelling in relation to prognosis of patients with chronic heart failure. Proceedings from American Heart Association's Scientific Session in Anaheim, California, 2017.
48. Sugano A., Seo Y., Ishizu T. Interaction between Mineralocorticoid Receptor Antagonist and soluble ST2 in Patients with Heart Failure and Preserved Ejection Fraction. Proceedings from American Heart Association's Scientific Session in Anaheim, California, 2017.
49. Sanchez-Mas J., Lax A., Asensio-Lopez M. del C. et al. Modulation of IL-33/ST2 system in postinfarction heart failure: Correlation with cardiac remodelling markers // Eur. J. Clin. Invest. 2014. V. 44. № 7. P. 643–651.
50. Tseng C.C.S., Huibers M.M.H., Gaykema L.H. et al. Soluble ST2 in end-stage heart failure, before and after support with a left ventricular assist device // ARPN J. Eng. Appl. Sci. 2017. V. 12. № 10. P. 3218–3221.
51. Kim S.H., Kim H.L., Lim W.H. et al. Soluble ST2 is a novel marker of aortic stiffness and arteriosclerosis measured by invasive hemodynamic study // Atherosclerosis. 2016. V. 252. № 2016. P. e165.
52. Miller A.M., Xu D., Asquith D.L. et al. IL-33 reduces the development of atherosclerosis // J. Exp. Med. 2008. V. 205. № 2. P. 339–346.
53. McLaren J.E., Michael D.R., Salter R.C. et al. IL-33 Reduces Macrophage Foam Cell Formation // J. Immunol. 2010. V. 185.  № 2. P. 1222–1229.
54. Martin P., Palmer G., Rodriguez E. et al. Atherosclerosis severity is not affected by a deficiency in IL-33 / ST2 signaling // 2015. V. 3. P. 239–246.