IL-25 Impact on Malignant B Cells Survival and T Cells Activation in Chronic Lymphocytic Leukemia
-
Mehrnoosh Pashei
,
Farahnaz Ghahremanfard
,
Ehsan Manouchehri Doulabi
,
Maral Hemmati
,
Fatemeh Pak
,
Parviz Kokhaei
Abstract
T cell dysregulation and shift to T helper 2 responses, boosting tumor microenvironment support, contributes to the survival of leukemic B cells in Chronic Lymphocytic Leukemia. Interleukin (IL)-25 is involved in the initiation of T helper 2 cell responses. Signal transduction of IL-25 begins with the heterodimer receptor (IL-17RA/IL-17RB). The presence of IL-25 in the tumor microenvironment may affect the supportive effects of T cells in the surrounding tumor cell environment. The purpose of this study was to evaluate the role of IL-25 in the biology of CLL.
IL-17RB expression in CD3+ and CD19+ cells was assessed in isolated peripheral blood mononuclear cells (PBMCs) of nine CLL patients and nine healthy subjects by real-time polymerase chain reaction and flow cytometry. B cells were positively enriched from PBMCs using magnetic-activated cell sorting (MACS). PBMCs and purified leukemic B cells were cultured with recombinant human IL-25 (20ng/ml) for 72 hours, then the viability and apoptosis of cultured cells were measured by MTT assay and AnnexinV/7AAD. Furthermore, the levels of CD69 expression on T lymphocytes and IL-17RB in T and B cells were determined by flow cytometry.
The basal level of IL-17RB expression in CLL patients was significantly higher than that in control individuals. In addition, the percentage of IL-17RB+/CD3+, IL-17RB+/CD19+ cells and CD69+/CD3+ cells increased after 72 hours of culture with IL-25 in CLL patients compared to healthy subjects. IL-25 also reduces the apoptosis rate of tumor cells.
We found that IL-25 could stimulate T cells in CLL patients and lower B cell death. This suggests that IL-25 might have a role in enhancing the survival of tumor cell by expressing receptors for inflammation, such as IL-17RB, and might be involved in the development of CLL.
1. Khan M, Saif A, Sandler S, Mirrakhimov AE. Idelalisib for the treatment of chronic lymphocytic leukemia. ISRN oncology. 2014;2014:931858. PubMed PMID: 25093123. Pubmed Central PMCID: PMC4003830. Epub 2014/08/06. eng.
2. Goldin LR, Slager SL. Familial CLL: genes and environment. Hematology Am Soc Hematol Educ Program. 2007;2007(1):339-45.
3. Collins RJ, Verschuer LA, Harmon BV, Prentice RL, Pope JH, Kerr JF. Spontaneous programmed death (apoptosis) of B‐chronic lymphocytic leukaemia cells following their culture in vitro. Br J Haematol. 1989;71(3):343-50.
4. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009 Oct 15;114(16):3367-75. PubMed PMID: 19636060. Epub 2009/07/29. eng.
5. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001;15(6):985-95.
6. Deng C, Peng N, Tang Y, Yu N, Wang C, Cai X, et al. Roles of IL-25 in type 2 inflammation and autoimmune pathogenesis. Frontiers in Immunology. 2021;12:691559.
7. Tian E, Sawyer JR, Largaespada DA, Jenkins NA, Copeland NG, Shaughnessy JD. Evi27 encodes a novel membrane protein with homology to the IL17 receptor. Oncogene. 2000;19(17):2098.
8. Lavorgna A, Matsuoka M, Harhaj EW. A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-κB activation and T-cell transformation. PLoS Pathog. 2014;10(10):e1004418.
9. Bastid J, Dejou C, Docquier A, Bonnefoy N. The emerging role of the IL-17B/IL-17RB pathway in cancer. Frontiers in immunology. 2020;11:718.
10. Song X, Qian Y. IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cellular signalling. 2013 Dec;25(12):2335-47. PubMed PMID: 23917206. Epub 2013/08/07. eng.
11. Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule induced following activation. Trends in immunology. 2005;26(3):136-40.
12. Scrivener S, Kaminski ER, Demaine A, Prentice AG. Analysis of the expression of critical activation/interaction markers on peripheral blood T cells in B‐cell chronic lymphocytic leukaemia: evidence of immune dysregulation. British journal of haematology. 2001;112(4):959-64.
13. Podhorecka M, Dmoszynska A, Rolinski J, Wasik E. T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia—the three-color flow cytometry analysis. Leukemia research. 2002;26(7):657-60.
14. Palma M, Gentilcore G, Heimersson K, Mozaffari F, Näsman-Glaser B, Young E, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. haematologica. 2017;102(3):562-72.
15. Wang Y-H, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC–activated Th2 memory cells. The Journal of experimental medicine. 2007;204(8):1837-47.
16. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-56.
17. Panayiotidis P, Ganeshaguru K, Jabbar SA, Hoffbrand AV. Interleukin‐4 inhibits apoptotic cell death and loss of the bcl‐2 protein in B‐chronic lymphocytic leukaemia cells in vitro. British journal of haematology. 1993;85(3):439-45.
18. Kiaii S, Kokhaei P, Mozaffari F, Rossmann E, Pak F, Moshfegh A, et al. T cells from indolent CLL patients prevent apoptosis of leukemic B cells in vitro and have altered gene expression profile. Cancer Immunology, Immunotherapy. 2013;62(1):51-63.
19. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073-81.
20. Yao X, Sun Y, Wang W, Sun Y. Interleukin (IL)‐25: Pleiotropic roles in asthma. Respirology. 2016;21(4):638-47.
21. Mombelli S, Cochaud S, Merrouche Y, Garbar C, Antonicelli F, Laprevotte E, et al. IL-17A and its homologs IL-25/IL-17E recruit the c-RAF/S6 kinase pathway and the generation of pro-oncogenic LMW-E in breast cancer cells. Scientific reports. 2015;5:11874.
22. Laprevotte E, Cochaud S, du Manoir S, Lapierre M, Dejou C, Philippe M, et al. The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway. Oncotarget. 2017;8(69):113360.
23. Wu H-H, Hwang-Verslues WW, Lee W-H, Huang C-K, Wei P-C, Chen C-L, et al. Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. Journal of Experimental Medicine. 2015;212(3):333-49.
24. Bie Q, Sun C, Gong A, Li C, Su Z, Zheng D, et al. Non-tumor tissue derived interleukin-17B activates IL-17RB/AKT/β-catenin pathway to enhance the stemness of gastric cancer. Scientific reports. 2016;6(1):1-12.
25. Caruso R, Stolfi C, Sarra M, Rizzo A, Fantini MC, Pallone F, et al. Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3. Blood. 2009;113(15):3512-9.
26. Bredo G, Storie J, Shrestha Palikhe N, Davidson C, Adams A, Vliagoftis H, et al. Interleukin‐25 initiates Th2 differentiation of human CD4+ T cells and influences expression of its own receptor. Immunity, inflammation and disease. 2015;3(4):455-68.
27. Kim MR, Manoukian R, Yeh R, Silbiger SM, Danilenko DM, Scully S, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production. Blood. 2002;100(7):2330-40.
28. Guo H-Z, Niu L-T, Qiang W-T, Chen J, Wang J, Yang H, et al. Leukemic IL-17RB signaling regulates leukemic survival and chemoresistance. The FASEB Journal. 2019:fj. 201900099R.
29. Younesi V, Nejatollahi F. Induction of anti-proliferative and apoptotic effects by anti-IL-25 receptor single chain antibodies in breast cancer cells. International immunopharmacology. 2014;23(2):624-32.
30. Benatar T, Cao MY, Lee Y, Lightfoot J, Feng N, Gu X, et al. IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo. Cancer Immunology, Immunotherapy. 2010;59(6):805-17.
31. Wong CK, Li PW, Lam CWK. Intracellular JNK, p38 MAPK and NF-κB regulate IL-25 induced release of cytokines and chemokines from costimulated T helper lymphocytes. Immunology letters. 2007;112(2):82-91.
32. Ferretti E, Di Carlo E, Ognio E, Fraternali-Orcioni G, Corcione A, Belmonte B, et al. IL-25 dampens the growth of human germinal center-derived B-cell non Hodgkin Lymphoma by curtailing neoangiogenesis. OncoImmunology. 2018;7(3):e1397249.
2. Goldin LR, Slager SL. Familial CLL: genes and environment. Hematology Am Soc Hematol Educ Program. 2007;2007(1):339-45.
3. Collins RJ, Verschuer LA, Harmon BV, Prentice RL, Pope JH, Kerr JF. Spontaneous programmed death (apoptosis) of B‐chronic lymphocytic leukaemia cells following their culture in vitro. Br J Haematol. 1989;71(3):343-50.
4. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009 Oct 15;114(16):3367-75. PubMed PMID: 19636060. Epub 2009/07/29. eng.
5. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001;15(6):985-95.
6. Deng C, Peng N, Tang Y, Yu N, Wang C, Cai X, et al. Roles of IL-25 in type 2 inflammation and autoimmune pathogenesis. Frontiers in Immunology. 2021;12:691559.
7. Tian E, Sawyer JR, Largaespada DA, Jenkins NA, Copeland NG, Shaughnessy JD. Evi27 encodes a novel membrane protein with homology to the IL17 receptor. Oncogene. 2000;19(17):2098.
8. Lavorgna A, Matsuoka M, Harhaj EW. A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-κB activation and T-cell transformation. PLoS Pathog. 2014;10(10):e1004418.
9. Bastid J, Dejou C, Docquier A, Bonnefoy N. The emerging role of the IL-17B/IL-17RB pathway in cancer. Frontiers in immunology. 2020;11:718.
10. Song X, Qian Y. IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cellular signalling. 2013 Dec;25(12):2335-47. PubMed PMID: 23917206. Epub 2013/08/07. eng.
11. Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule induced following activation. Trends in immunology. 2005;26(3):136-40.
12. Scrivener S, Kaminski ER, Demaine A, Prentice AG. Analysis of the expression of critical activation/interaction markers on peripheral blood T cells in B‐cell chronic lymphocytic leukaemia: evidence of immune dysregulation. British journal of haematology. 2001;112(4):959-64.
13. Podhorecka M, Dmoszynska A, Rolinski J, Wasik E. T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia—the three-color flow cytometry analysis. Leukemia research. 2002;26(7):657-60.
14. Palma M, Gentilcore G, Heimersson K, Mozaffari F, Näsman-Glaser B, Young E, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. haematologica. 2017;102(3):562-72.
15. Wang Y-H, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC–activated Th2 memory cells. The Journal of experimental medicine. 2007;204(8):1837-47.
16. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-56.
17. Panayiotidis P, Ganeshaguru K, Jabbar SA, Hoffbrand AV. Interleukin‐4 inhibits apoptotic cell death and loss of the bcl‐2 protein in B‐chronic lymphocytic leukaemia cells in vitro. British journal of haematology. 1993;85(3):439-45.
18. Kiaii S, Kokhaei P, Mozaffari F, Rossmann E, Pak F, Moshfegh A, et al. T cells from indolent CLL patients prevent apoptosis of leukemic B cells in vitro and have altered gene expression profile. Cancer Immunology, Immunotherapy. 2013;62(1):51-63.
19. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073-81.
20. Yao X, Sun Y, Wang W, Sun Y. Interleukin (IL)‐25: Pleiotropic roles in asthma. Respirology. 2016;21(4):638-47.
21. Mombelli S, Cochaud S, Merrouche Y, Garbar C, Antonicelli F, Laprevotte E, et al. IL-17A and its homologs IL-25/IL-17E recruit the c-RAF/S6 kinase pathway and the generation of pro-oncogenic LMW-E in breast cancer cells. Scientific reports. 2015;5:11874.
22. Laprevotte E, Cochaud S, du Manoir S, Lapierre M, Dejou C, Philippe M, et al. The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway. Oncotarget. 2017;8(69):113360.
23. Wu H-H, Hwang-Verslues WW, Lee W-H, Huang C-K, Wei P-C, Chen C-L, et al. Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. Journal of Experimental Medicine. 2015;212(3):333-49.
24. Bie Q, Sun C, Gong A, Li C, Su Z, Zheng D, et al. Non-tumor tissue derived interleukin-17B activates IL-17RB/AKT/β-catenin pathway to enhance the stemness of gastric cancer. Scientific reports. 2016;6(1):1-12.
25. Caruso R, Stolfi C, Sarra M, Rizzo A, Fantini MC, Pallone F, et al. Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3. Blood. 2009;113(15):3512-9.
26. Bredo G, Storie J, Shrestha Palikhe N, Davidson C, Adams A, Vliagoftis H, et al. Interleukin‐25 initiates Th2 differentiation of human CD4+ T cells and influences expression of its own receptor. Immunity, inflammation and disease. 2015;3(4):455-68.
27. Kim MR, Manoukian R, Yeh R, Silbiger SM, Danilenko DM, Scully S, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production. Blood. 2002;100(7):2330-40.
28. Guo H-Z, Niu L-T, Qiang W-T, Chen J, Wang J, Yang H, et al. Leukemic IL-17RB signaling regulates leukemic survival and chemoresistance. The FASEB Journal. 2019:fj. 201900099R.
29. Younesi V, Nejatollahi F. Induction of anti-proliferative and apoptotic effects by anti-IL-25 receptor single chain antibodies in breast cancer cells. International immunopharmacology. 2014;23(2):624-32.
30. Benatar T, Cao MY, Lee Y, Lightfoot J, Feng N, Gu X, et al. IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo. Cancer Immunology, Immunotherapy. 2010;59(6):805-17.
31. Wong CK, Li PW, Lam CWK. Intracellular JNK, p38 MAPK and NF-κB regulate IL-25 induced release of cytokines and chemokines from costimulated T helper lymphocytes. Immunology letters. 2007;112(2):82-91.
32. Ferretti E, Di Carlo E, Ognio E, Fraternali-Orcioni G, Corcione A, Belmonte B, et al. IL-25 dampens the growth of human germinal center-derived B-cell non Hodgkin Lymphoma by curtailing neoangiogenesis. OncoImmunology. 2018;7(3):e1397249.
| Files | ||
| Issue | Vol 22 No 3 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i3.13058 | |
| Keywords | ||
| : Chronic lymphocytic leukemia Interleukin-25 Tumor microenvironment T helper 2 cells | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Pashei M, Ghahremanfard F, Manouchehri Doulabi E, Hemmati M, Pak F, Kokhaei P. IL-25 Impact on Malignant B Cells Survival and T Cells Activation in Chronic Lymphocytic Leukemia. Iran J Allergy Asthma Immunol. 2023;22(3):299-311.
