IL-33 – positive or negative role in cancer progression?
Joanna Jarosz 1 , Diana Papiernik 2 , Joanna Wietrzyk 1Abstract
Interleukin-33 (IL-33) is a IL-1 family member of cytokines which binds the ST2 (suppression of tumorigenicity 2) receptor. This cytokine has a dual function. It may act both as a traditional cytokine and as an intracellular nuclear factor. IL-33 plays a role in many diseases such as: allergy, inflammatory diseases, diabetes and heart diseases. The role of IL-33 in the development of cancer has been intensively studied in recent years and researchers observe both its pro- -and anti-cancer effects. IL-33 promotes the development of tumors by affecting expression of cytokines promoting proliferation, angiogenesis, migration, matrix remodeling, the inhibition of apoptosis and recruitment of individual cells of the immune system. Antitumor action of IL-33 is carried out by recruiting and activating CD8+T lymphocytes, natural killer (NK) cells and by promoting second type immune response by the type 2 innate lymphoid cells (ILC2). Despite numerous studies on the role of IL-33 in the development of cancer, we still do not fully understand the mechanisms by which IL-33 impacts the development and malignancy of various types of cancers. This review summarizes the dual role of IL-33 in the development of the most common cancers in the world to better understand its importance in the carcinogenesis.
References
- 1. Afferni C., Buccione C., Andreone S., Galdiero M.R., Varricchi G.,Marone G., Mattei F., Schiavoni G.: The pleiotropic immunomodulatoryfunctions of IL-33 and its implications in tumor immunity.Front. Immunol., 2018; 9: 2601 2 Akimoto M., Hayashi J.I., Nakae S., Saito H., Takenaga K.: Interleukin- 33 enhances programmed oncosis of ST2L-positive low-metastaticcells in the tumour microenvironment of lung cancer. CellDeath Dis., 2016; 7: e2057
Google Scholar - 2. immune responses. J. Allergy Clin. Immunol., 2016; 137: 1545–1556
Google Scholar - 3. Akimoto M., Maruyama R., Takamaru H., Ochiya T., Takenaga K.:Soluble IL-33 receptor sST2 inhibits colorectal cancer malignantgrowth by modifying the tumour microenvironment. Nat. Commun.,2016; 7: 13589
Google Scholar - 4. Akimoto M., Takenaga K.: Role of the IL-33/ST2L axis in colorectalcancer progression. Cell. Immunol., 2019; 343: 103740
Google Scholar - 5. Ameri A.H., Moradi Tuchayi S., Zaalberg A., Park J.H., Ngo K.H.,Li T., Lopez E., Colonna M., Lee R.T., Mino-Kenudson M., Demehri S.:IL-33/regulatory T cell axis triggers the development of a tumor–promoting immune environment in chronic inflammation. Proc.Natl. Acad. Sci. USA, 2019; 116: 2646–2651
Google Scholar - 6. Bae S., Kang T., Hong J., Lee S., Choi J., Jhun H., Kwak A., HongK., Kim E., Jo S., Kim S.: Contradictory functions (activation/termination)of neutrophil proteinase 3 enzyme (PR3) in interleukin‐33biological activity. J. Biol. Chem., 2012; 287: 8205–8213
Google Scholar - 7. Baekkevold E.S., Roussigné M., Yamanaka T., Johansen F.E., JahnsenF.L., Amalric F., Brandtzaeg P., Erard M., Haraldsen G., Girard J.P.:Molecular characterization of NF-HEV, a nuclear factor preferentiallyexpressed in human high endothelial venules. Am. J. Pathol.,2003; 163: 69–79
Google Scholar - 8. Bessa J., Meyer C.A., de Vera Mudry M.C., Schlicht S., Smith S.H.,Iglesias A., Cote-Sierra J.: Altered subcellular localization of IL‐33 leadsto non‐resolving lethal inflammation. J. Autoimmun., 2014; 55: 33–41
Google Scholar - 9. Byrne S.N., Beaugie C., O’Sullivan C., Leighton S., Halliday G.M.:The immune-modulating cytokine and endogenous Alarmin interleukin- 33 is upregulated in skin exposed to inflammatory UVB radiation.Am. J. Pathol., 2011; 179: 211–222
Google Scholar - 10. Carriere V., Roussel L., Ortega N., Lacorre D.A., Americh L., AguilarL., Bouche G., Girard J.P.: IL‐33, the IL‐1‐like cytokine ligand forST2 receptor, is a chromatin‐associated nuclear factor in vivo. Proc.Natl. Acad. Sci. USA, 2007; 104: 282–287
Google Scholar - 11. Cayrol C., Girard J.P.: The IL‐1‐like cytokine IL‐33 is inactivated aftermaturation by caspase‐1. Proc. Natl. Acad. Sci. USA, 2009; 106: 9021–9026
Google Scholar - 12. Cayrol C., Girard J.P.: Interleukin‐33 (IL‐33): A nuclear cytokinefrom the IL‐1 family. Immunol. Rev., 2018; 281: 154–168
Google Scholar - 13. Cohen E.S., Scott I.C., Majithiya J.B., Rapley L., Kemp B.P., EnglandE., Rees D.G., Overed-Sayer C.L., Woods J., Bond N.J., Veyssier C.S.,Embrey K.J., Sims D.A., Snaith M.R., Vousden K.A. i wsp.: Oxidationof the alarmin IL‐33 regulates ST2‐dependent inflammation. Nat.Commun., 2015; 6: 8327
Google Scholar - 14. Cui G., Qi H., Gundersen M.D., Yang H., Christiansen I., SørbyeS.W., Goll R., Florholmen J.: Dynamics of the IL-33/ST2 network inthe progression of human colorectal adenoma to sporadic colorectalcancer. Cancer Immunol. Immunother., 2015; 64: 181–190
Google Scholar - 15. Dominguez D., Ye C., Geng Z., Chen S., Fan J., Qin L., Long A., WangL., Zhang Z., Zhang Y., Fang D., Kuzel T.M., Zhang B.: Exogenous IL- 33 restores dendritic cell activation and maturation in establishedcancer. J. Immunol., 2017; 198: 1365–1375
Google Scholar - 16. Eissmann M.F., Dijkstra C., Wouters M.A., Baloyan D., MouradovD., Nguyen P.M., Davalos-Salas M., Putoczki T.L., Sieber O.M., MariadasonJ.M., Ernst M., Masson F.: Interleukin 33 signaling restrainssporadic colon cancer in an interferon-γ-dependent manner. CancerImmunol. Res., 2018; 6: 409–421
Google Scholar - 17. Fang M., Li Y., Huang K., Qi S., Zhang J., Zgodzinski W., MajewskiM., Wallner G., Gozdz S., Macek P., Kowalik A., Pasiarski M., GrywalskaE., Vatan L., Nagarsheth N. i wsp.: IL33 promotes colon cancer cellstemness via JNK activation and macrophage recruitment. CancerRes., 2017; 77: 2735–2745
Google Scholar - 18. Fournié J.J., Poupot M.: The pro-tumorigenic IL-33 involved inantitumor immunity: A yin and yang cytokine. Front. Immunol.,2018; 9: 2506
Google Scholar - 19. Gao K., Li X., Zhang L., Bai L., Dong W., Gao K., Shi G., Xia X., WuL., Zhang L.: Transgenic expression of IL-33 activates CD8+ T cells andNK cells and inhibits tumor growth and metastasis in mice. CancerLett., 2013; 335: 463–471
Google Scholar - 20. Gao X., Wang X., Yang Q., Zhao X., Wen W., Li G., Lu J., Qin W.,Qi Y., Xie F., Jiang J., Wu C., Zhang X., Chen X., Turnquist H., Zhu Y.,Lu B.: Tumoral expression of IL-33 inhibits tumor growth and modifiesthe tumor microenvironment through CD8+ T and NK cells. J.Immunol., 2015; 194: 438–445
Google Scholar - 21. Halvorsen E.C., Franks S.E., Wadsworth B.J., Harbourne B.T., CederbergR.A., Steer C.A., Martinez-Gonzalez I., Calder J., LockwoodW.W., Bennewith K.L.: IL-33 increases ST2+ Tregs and promotes metastatictumour growth in the lungs in an amphiregulin-dependentmanner. Oncoimmunology, 2018; 8: e1527497
Google Scholar - 22. Hayakawa H., Hayakawa M., Kume A., Tominaga S.: Soluble ST2blocks interleukin‐33 signaling in allergic airway inflammation. J.Biol. Chem., 2007; 282: 26369–26380
Google Scholar - 23. He Z., Chen L., Souto F.O., Canasto-Chibuque C., Bongers G., DeshpandeM., Harpaz N., Ko H.M., Kelley K., Furtado G.C., Lira S.A.:Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc-Min/+ mice. Sci. Rep., 2017; 7: 5520
Google Scholar - 24. He Z., Song J., Hua J., Yang M., Ma Y., Yu T., Feng J., Liu B., WangX., Li Y., Li J.: Mast cells are essential intermediaries in regulatingIL-33/ST2 signaling for an immune network favorable to mucosal healingin experimentally inflamed colons. Cell Death Dis., 2018; 9: 1173
Google Scholar - 25. Hollande C., Boussier J., Ziai J., Nozawa T., Bondet V., Phung W.,Lu B., Duffy D., Paradis V., Mallet V., Eberl G., Sandoval W., SchartnerJ.M., Pol S., Barreira da Silva R., Albert M.L.: Inhibition of the dipeptidylpeptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediatedcontrol of tumor growth. Nat. Immunol., 2019; 20: 257–264
Google Scholar - 26. Hristova M., Habibovic A., Veith C., Janssen-Heininger Y.M., DixonA.E., Geiszt M., van der Vliet A.: Airway epithelial dual oxidase 1 mediates allergen‐induced IL‐33 secretion and activation of type
Google Scholar - 27. Hu H., Sun J., Wang C., Bu X., Liu X., Mao Y., Wang H.: IL-33 facilitatesendocrine resistance of breast cancer by inducing cancer stemcell properties. Biochem. Biophys. Res. Commun., 2017; 485: 643–650
Google Scholar - 28. Hu L.A., Fu Y., Zhang D.N., Zhang J.: Serum IL-33 as a diagnosticand prognostic marker in non-small cell lung cancer. Asian Pac. J.Cancer Prev., 2013; 14: 2563–2566
Google Scholar - 29. Iwahana H., Hayakawa M., Kuroiwa K., Tago K., Yanagisawa K.,Noji S., Tominaga S.: Molecular cloning of the chicken ST2 gene,a novel variant form of the ST2 gene product, ST2LV. Biochim. Biophys.Acta, 2004; 1681: 1–14
Google Scholar - 30. Jovanovic I., Radosavljevic G., Mitrovic M., Juranic V.L., McKenzieA.N., Arsenijevic N., Jonjic S., Lukic M.L.: ST2 deletion enhancesinnate and acquired immunity to murine mammary carcinoma. Eur.J. Immunol., 2011; 41: 1902–1912
Google Scholar - 31. Jovanovic I.P., Pejnovic N.N., Radosavljevic G.D., Pantic J.M.,Milovanovic M.Z., Arsenijevic N.N., Lukic M.L.: Interleukin-33/ST2axis promotes breast cancer growth and metastases by facilitatingintratumoral accumulation of immunosuppressive and innate lymphoidcells. Int. J. Cancer, 2014; 134: 1669–1682
Google Scholar - 32. Kakkar R., Lee R.T.: The IL-33/ST2 pathway: Therapeutic targetand novel biomarker. Nat. Rev. Drug Discov., 2008; 7: 827–840 33 Kim J., Kim W., Moon U.J., Kim H.J., Choi H.J., Sin J.I., Park N.H.,Cho H.R., Kwon B.: Intratumorally establishing type 2 innate lymphoidcells blocks tumor growth. J. Immunol., 2016; 196: 2410–2423
Google Scholar - 33. stimulation enhances lipopolysaccharide-mediated macrophageactivation. PLoS One, 2011; 6: e18404
Google Scholar - 34. Kouzaki H., Iijima K., Kobayashi T., O’Grady S.M., Kita H.: Thedanger signal, extracellular ATP, is a sensor for an airborne allergenand triggers IL‐33 release and innate Th2‐type responses. J. Immunol.,2011; 186: 4375–4387
Google Scholar - 35. Lefrançais E., Roga S., Gautier V., Gonzalez-de-Peredo A., MonsarratB., Girard J.P., Cayrol C.: IL‐33 is processed into mature bioactiveforms by neutrophil elastase and cathepsin G. Proc. Natl. Acad.Sci. USA, 2012; 109: 1673–1678
Google Scholar - 36. Li X., Lv Q., Feng Y., Gu Y., Xia R., Ma J., He H., Zhu Y.: Interleukin- 33 a potential cytokine expressed in tumor microenvironmentinvolves in antitumor immunotherapy through facilitates CD8+ Tcells. J. Interferon Cytokine Res., 2018; 38: 491–499
Google Scholar - 37. Li Y., Shi J., Qi S., Zhang J., Peng D., Chen Z., Wang G., Wang Z.,Wang L.: IL-33 facilitates proliferation of colorectal cancer dependenton COX2/PGE2. J. Exp. Clin. Cancer Res., 2018; 37: 196
Google Scholar - 38. Liew F.Y., Girard J.P., Turnquist H.R.: Interleukin‐33 in healthand disease. Nat. Rev. Immunol., 2016; 16: 676‐689
Google Scholar - 39. Lingel A., Weiss T.M., Niebuhr M., Pan B., Appleton B.A., WiesmannC., Bazan J.F., Fairbrother W.J.: Structure of IL‐33 and its interactionwith the ST2 and IL‐1RAcP receptors – insight into heterotrimericIL‐1 signaling complexes. Structure, 2009; 17: 1398–1410
Google Scholar - 40. Liu X.., Hammel M., He Y., Tainer J.A., Jeng U.S., Zhang L., WangS., Wang X.: Structural insights into the interaction of IL‐33 with itsreceptors. Proc. Natl. Acad. Sci. USA, 2013; 110: 14918–14923
Google Scholar - 41. Liu X., Zhu L., Lu X., Bian H., Wu X., Yang W., Qin Q.: IL-33/ST2pathway contributes to metastasis of human colorectal cancer. Biochem.Biophys. Res. Commun., 2014; 453: 486–492
Google Scholar - 42. Long A., Dominguez D., Qin L., Chen S., Fan J., Zhang M., Fang D.,Zhang Y., Kuzel T.M., Zhang B.: Type 2 innate lymphoid cells impedeIL-33-mediated tumor suppression. J. Immunol., 2018; 201: 3456–3464
Google Scholar - 43. Lu D.P., Zhou X.Y., Yao L.T., Liu C.G., Ma W., Jin F., Wu Y.F.: Serumsoluble ST2 is associated with ER-positive breast cancer. BMCCancer, 2014; 14: 198
Google Scholar - 44. Lucarini V., Ziccheddu G., Macchia I., La Sorsa V., Peschiaroli F.,Buccione C., Sistigu A., Sanchez M., Andreone S., D’Urso M.T., SpadaM., Macchia D., Afferni C., Mattei F., Schiavoni G.: IL-33 restricts tumorgrowth and inhibits pulmonary metastasis in melanoma-bearingmice through eosinophils. Oncoimmunology, 2017; 6: e1317420
Google Scholar - 45. Malik A., Sharma D., Zhu Q., Karki R., Guy C.S., Vogel P., KannegantiT.D.: IL-33 regulates the IgA-microbiota axis to restrain IL-1α-dependentcolitis and tumorigenesis. J. Clin. Invest., 2016; 126: 4469–4481
Google Scholar - 46. Maywald R.L., Doerner S.K., Pastorelli L., De Salvo C., BentonS.M., Dawson E.P., Lanza D.G., Berger N.A., Markowitz S.D., Lenz H.J.,Nadeau J.H., Pizarro T.T., Heaney J.D.: IL-33 activates tumor stromato promote intestinal polyposis. Proc. Natl. Acad. Sci. USA, 2015;112: E2487–E2496
Google Scholar - 47. Mertz K.D., Mager L.F., Wasmer M.H., Thiesler T., Koelzer V.H.,Ruzzante G., Joller S., Murdoch J.R., Brümmendorf T., Genitsch V.,Lugli A., Cathomas G., Moch H., Weber A., Zlobec I.: The IL-33/ST2pathway contributes to intestinal tumorigenesis in humans andmice. Oncoimmunology, 2015; 5: e1062966
Google Scholar - 48. Milosavljevic M.Z., Jovanovic I.P., Pejnovic N.N., Mitrovic S.L.,Arsenijevic N.N., Simovic Markovic B.J., Lukic M.L.: Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammarycarcinoma. Oncotarget, 2016; 7: 18106–18115
Google Scholar - 49. Moussion C., Ortega N., Girard J.P.: The IL‐1‐like cytokine IL‐33is constitutively expressed in the nucleus of endothelial cells andepithelial cells in vivo: A novel ‘alarmin’? PLoS One, 2008; 3: e3331
Google Scholar - 50. O’Donnell C., Mahmoud A., Keane J., Murphy C., White D., CareyS., O’Riordain M., Bennett M.W., Brint E., Houston A.: An antitumorigenicrole for the IL-33 receptor, ST2L, in colon cancer. Br. J. Cancer,2016; 114: 37–43
Google Scholar - 51. Ohno T., Oboki K., Morita H., Kajiwara N., Arae K., Tanaka S.,Ikeda M., Iikura M., Akiyama T., Inoue J., Matsumoto K., Sudo K.,Azuma M., Okumura K., Kamradt T., Saito H., Nakae S.: Paracrine IL-
Google Scholar - 52. Onda H., Kasuya H., Takakura K., Hori T., Imaizumi T., TakeuchiT., Inoue I., Takeda J.: Identification of genes differentially expressedin canine vasospastic cerebral arteries after subarachnoid hemorrhage.J. Cerebr. Blood Flow Metab., 1999; 19: 1279–1288
Google Scholar - 53. Patel M., Horgan P.G., McMillan D.C., Edwards J.: NF-κB pathwaysin the development and progression of colorectal cancer. Transl.Res., 2018; 197: 43–56
Google Scholar - 54. Pichery M., Mirey E., Mercier P., Lefrancais E., Dujardin A., OrtegaN., Girard J.P: Endogenous IL‐33 is highly expressed in mouse epithelialbarrier tissues, lymphoid organs, brain, embryos, and inflamedtissues. In situ analysis using a novel Il‐33‐LacZ gene trap reporterstrain. J. Immunol., 2012; 188: 3488–3495
Google Scholar - 55. Roussel L., Erard M., Cayrol C., Girard J.P.: Molecular mimicrybetween IL‐33 and KSHV for attachment to chromatin through theH2A‐H2B acidic pocket. EMBO Rep., 2008; 9: 1006–1012
Google Scholar - 56. Saadalla A.M., Osman A., Gurish M.F., Dennis K.L., Blatner N.R.,Pezeshki A., McNagny K.M., Cheroutre H., Gounari F., Khazaie K.:Mast cells promote small bowel cancer in a tumor stage-specificand cytokine-dependent manner. Proc. Natl. Acad. Sci. USA, 2018;115: 1588–1592
Google Scholar - 57. Saranchova I., Han J., Huang H., Fenninger F., Choi K.B., MunroL., Pfeifer C., Welch I., Wyatt A.W., Fazli L., Gleave M.E., Jefferies W.A.:Discovery of a metastatic immune escape mechanism initiated bythe loss of expression of the tumour biomarker interleukin-33. Sci.Rep., 2016; 6: 30555
Google Scholar - 58. Schiering C., Krausgruber T., Chomka A., Fröhlich A., AdelmannK., Wohlfert E.A., Pott J., Griseri T., Bollrath J., Hegazy A.N., HarrisonO.J., Owens B.M.J., Löhning M., Belkaid Y., Fallon P.G., Powrie F.: Thealarmin IL-33 promotes regulatory T-cell function in the intestine.Nature, 2014; 513: 564–568
Google Scholar - 59. Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahanT.K., Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., BazanJ.F., Kastelein R.A.: IL-33, an interleukin-1-like cytokine that signalsvia the IL-1 receptor-related protein ST2 and induces T helper type2-associated cytokines. Immunity, 2005; 23: 479–490
Google Scholar - 60. Shimokawa C., Kanaya T., Hachisuka M., Ishiwata K., Hisaeda H.,Kurashima Y., Kiyono H., Yoshimoto T., Kaisho T., Ohno H.: Mast cellsare crucial for induction of group 2 innate lymphoid cells and clearanceof Helminth infections. Immunity, 2017; 46: 863–874
Google Scholar - 61. Siegel R.L., Miller K.D., Jemal A.: Cancer statistics, 2019. CA CancerJ. Clin., 2019; 69: 7–34
Google Scholar - 62. Sun M., Bai Y., Zhao S., Liu X., Gao Y., Wang L., Liu B., Ma D., MaC.: Gram-negative bacteria facilitate tumor progression throughTLR4/IL-33 pathway in patients with non-small-cell lung cancer.Oncotarget, 2018; 9: 13462–13473
Google Scholar - 63. Tominaga S.: A putative protein of a growth specific cDNA fromBALB/c-3T3 cells is highly similar to the extracellular portion of mouseinterleukin 1 receptor. FEBS Lett., 1989; 258: 301–304
Google Scholar - 64. Tominaga S.I., Kuroiwa K., Tago K., Iwahana H., Yanagisawa K.,Komatsu N.: Presence and expression of a novel variant form of ST2gene product in human leukemic cell line UT-7/GM. Biochem. Biophys.Res. Commun., 1999; 264: 14–18
Google Scholar - 65. Uchida M., Anderson E.L., Squillace D.L., Patil N., Maniak P.J., IijimaK., Kita H., O’Grady S.M.: Oxidative stress serves as a key checkpointfor IL‐33 release by airway epithelium. Allergy, 2017; 72: 1521–1531
Google Scholar - 66. Waern I., Lundequist A., Pejler G., Wernersson S.: Mast cell chymasemodulates IL‐33 levels and controls allergic sensitization in dust‐miteinduced airway inflammation. Mucosal. Immunol., 2013; 6: 911–920
Google Scholar - 67. Wang C., Chen Z., Bu X., Han Y., Shan S., Ren T., Song W.: IL-33signaling fuels outgrowth and metastasis of human lung cancer.Biochem. Biophys. Res. Commun., 2016; 479: 461–468
Google Scholar - 68. Wang K., Shan S., Yang Z., Gu X., Wang Y., Wang C., Ren T.: IL-33 blockadesuppresses tumor growth of human lung cancer through direct andindirect pathways in a preclinical model. Oncotarget, 2017; 8: 68571–68582
Google Scholar - 69. Xiaoli Z., Jin C., Hong J., Le C., Min W., Wei Z.: Up-regulation ofinterleukin-33 serum levels in metastatic prostate cancer Am. J.BioMed., 2014; 2: 928–939
Google Scholar - 70. Xu J., Qiu T., Li X. Zhou Y., Zhou P.: Role of IL-33 and ST2 signalingand inflammatory responses in non-small cell lung cancer. Trop.J. Pharm. Res., 2018; 17: 767–771
Google Scholar - 71. Yang M., Feng Y., Yue C., Xu B., Chen L., Jiang J., Lu B., Zhu Y.:Lower expression level of IL-33 is associated with poor prognosis ofpulmonary adenocarcinoma. PLoS One, 2018; 13: e0193428
Google Scholar - 72. Yang Z., Gao X., Wang J., Xu L., Zheng Y., Xu Y.: Interleukin-33enhanced the migration and invasiveness of human lung cancercells. Onco Targets Ther., 2018; 11: 843–849
Google Scholar - 73. Yang Z.P., Ling D.Y., Xie Y.H., Wu W.X., Li J.R., Jiang J., Zheng J.L.,Fan Y.H., Zhang Y.: The association of serum IL-33 and sST2 withbreast cancer. Dis. Markers, 2015; 2015: 516895
Google Scholar - 74. Zhang Y., Davis C., Shah S., Hughes D., Ryan J.C., Altomare D.,Peña M.M.: IL-33 promotes growth and liver metastasis of colorectalcancer in mice by remodeling the tumor microenvironment andinducing angiogenesis. Mol. Carcinog., 2017; 56: 272–287
Google Scholar