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. 1994 Jan 1;179(1):91–99. doi: 10.1084/jem.179.1.91

Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells

PMCID: PMC2191337  PMID: 8270886

Abstract

Recent studies have established that interleukin (IL)-10 induces growth and most notably differentiation of normal human B lymphocytes. We studied here the effects of IL-10 on the proliferation and survival of B-chronic lymphocytic leukemia (B-CLL) cells. IL-10 was found to inhibit 54-96% of the spontaneous tritiated thymidine incorporation observed in 3 of 12 B-CLL samples. Furthermore, IL-10 decreased the viable cell recovery of all five B-CLL samples tested, irrespective of whether cells were spontaneously synthesizing DNA or not. After 1 wk, B- CLL populations cultured with IL-10 were lost while those cultured without IL-10 survived. Flow cytometric analysis, DNA gel electrophoresis, and Giemsa staining all revealed that IL-10 induced B- CLL cells to die from apoptosis. This IL-10-mediated apoptosis was dose dependent and specific as it could be inhibited by a neutralizing anti- IL-10 antibody. B-CLL cells undergoing apoptosis in response to IL-10 showed decreased Bcl-2 protein levels. Addition of IL-2, IL-4, interferon gamma, and anti-CD40 monoclonal antibody prevented the IL-10- mediated apoptosis of B-CLL cells. None of the malignant B cell populations obtained from eight non-Hodgkin's lymphomas and three hairy cell leukemias underwent apoptosis after IL-10 treatment, thus suggesting that the apoptotic effect of IL-10 is specific for B-CLL cells. Thus, IL-10 inhibits the DNA synthesis and most notably the survival of B-CLL cells, findings that call for considering IL-10 in the immunotherapy of chemoresistant B-CLL.

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Selected References

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  1. Banchereau J., Rousset F. Human B lymphocytes: phenotype, proliferation, and differentiation. Adv Immunol. 1992;52:125–262. doi: 10.1016/s0065-2776(08)60876-7. [DOI] [PubMed] [Google Scholar]
  2. Benjamin D., Knobloch T. J., Dayton M. A. Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10. Blood. 1992 Sep 1;80(5):1289–1298. [PubMed] [Google Scholar]
  3. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  4. Burdin N., Péronne C., Banchereau J., Rousset F. Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med. 1993 Feb 1;177(2):295–304. doi: 10.1084/jem.177.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buschle M., Campana D., Carding S. R., Richard C., Hoffbrand A. V., Brenner M. K. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993 Jan 1;177(1):213–218. doi: 10.1084/jem.177.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collins R. J., Verschuer L. A., Harmon B. V., Prentice R. L., Pope J. H., Kerr J. F. Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro. Br J Haematol. 1989 Mar;71(3):343–350. doi: 10.1111/j.1365-2141.1989.tb04290.x. [DOI] [PubMed] [Google Scholar]
  8. Cordingley F. T., Bianchi A., Hoffbrand A. V., Reittie J. E., Heslop H. E., Vyakarnam A., Turner M., Meager A., Brenner M. K. Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies. Lancet. 1988 Apr 30;1(8592):969–971. doi: 10.1016/s0140-6736(88)91782-5. [DOI] [PubMed] [Google Scholar]
  9. Dancescu M., Rubio-Trujillo M., Biron G., Bron D., Delespesse G., Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 1992 Nov 1;176(5):1319–1326. doi: 10.1084/jem.176.5.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dighiero G., Travade P., Chevret S., Fenaux P., Chastang C., Binet J. L. B-cell chronic lymphocytic leukemia: present status and future directions. French Cooperative Group on CLL. Blood. 1991 Oct 15;78(8):1901–1914. [PubMed] [Google Scholar]
  12. Dive C., Gregory C. D., Phipps D. J., Evans D. L., Milner A. E., Wyllie A. H. Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochim Biophys Acta. 1992 Feb 3;1133(3):275–285. doi: 10.1016/0167-4889(92)90048-g. [DOI] [PubMed] [Google Scholar]
  13. Emilie D., Touitou R., Raphael M., Peuchmaur M., Devergnee O., Rea D., Coumbraras J., Crevon M. C., Edelman L., Joab I. In vivo production of interleukin-10 by malignant cells in AIDS lymphomas. Eur J Immunol. 1992 Nov;22(11):2937–2942. doi: 10.1002/eji.1830221127. [DOI] [PubMed] [Google Scholar]
  14. Fanidi A., Harrington E. A., Evan G. I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992 Oct 8;359(6395):554–556. doi: 10.1038/359554a0. [DOI] [PubMed] [Google Scholar]
  15. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fluckiger A. C., Garrone P., Durand I., Galizzi J. P., Banchereau J. Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes. J Exp Med. 1993 Nov 1;178(5):1473–1481. doi: 10.1084/jem.178.5.1473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Garcia I., Martinou I., Tsujimoto Y., Martinou J. C. Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science. 1992 Oct 9;258(5080):302–304. doi: 10.1126/science.1411528. [DOI] [PubMed] [Google Scholar]
  18. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gregory C. D., Dive C., Henderson S., Smith C. A., Williams G. T., Gordon J., Rickinson A. B. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature. 1991 Feb 14;349(6310):612–614. doi: 10.1038/349612a0. [DOI] [PubMed] [Google Scholar]
  20. Hivroz C., Grillot-Courvalin C., Brouet J. C., Seligmann M. Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2. Eur J Immunol. 1986 Aug;16(8):1001–1004. doi: 10.1002/eji.1830160821. [DOI] [PubMed] [Google Scholar]
  21. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  22. Kocks C., Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol. 1989;7:537–559. doi: 10.1146/annurev.iy.07.040189.002541. [DOI] [PubMed] [Google Scholar]
  23. Liu Y. J., Joshua D. E., Williams G. T., Smith C. A., Gordon J., MacLennan I. C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  24. McConkey D. J., Aguilar-Santelises M., Hartzell P., Eriksson I., Mellstedt H., Orrenius S., Jondal M. Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells. J Immunol. 1991 Feb 1;146(3):1072–1076. [PubMed] [Google Scholar]
  25. Miyazaki I., Cheung R. K., Dosch H. M. Viral interleukin 10 is critical for the induction of B cell growth transformation by Epstein-Barr virus. J Exp Med. 1993 Aug 1;178(2):439–447. doi: 10.1084/jem.178.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  27. Ostlund L., Einhorn S., Robèrt K. H., Juliusson G., Biberfeld P. Chronic B-lymphocytic leukemia cells proliferate and differentiate following exposure to interferon in vitro. Blood. 1986 Jan;67(1):152–159. [PubMed] [Google Scholar]
  28. Rolink A., Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. doi: 10.1016/0092-8674(91)90032-t. [DOI] [PubMed] [Google Scholar]
  29. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schena M., Larsson L. G., Gottardi D., Gaidano G., Carlsson M., Nilsson K., Caligaris-Cappio F. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood. 1992 Jun 1;79(11):2981–2989. [PubMed] [Google Scholar]
  31. Schmid D. S., Hornung R., McGrath K. M., Paul N., Ruddle N. H. Target cell DNA fragmentation is mediated by lymphotoxin and tumor necrosis factor. Lymphokine Res. 1987 Summer;6(3):195–202. [PubMed] [Google Scholar]
  32. Takeda Y., Watanabe H., Yonehara S., Yamashita T., Saito S., Sendo F. Rapid acceleration of neutrophil apoptosis by tumor necrosis factor-alpha. Int Immunol. 1993 Jun;5(6):691–694. doi: 10.1093/intimm/5.6.691. [DOI] [PubMed] [Google Scholar]
  33. Tsujimoto Y., Finger L. R., Yunis J., Nowell P. C., Croce C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984 Nov 30;226(4678):1097–1099. doi: 10.1126/science.6093263. [DOI] [PubMed] [Google Scholar]
  34. Vazquez A., Auffredou M. T., Chaouchi N., Taieb J., Sharma S., Galanaud P., Leca G. Differential inhibition of interleukin 2- and interleukin 4-mediated human B cell proliferation by ionomycin: a possible regulatory role for apoptosis. Eur J Immunol. 1991 Oct;21(10):2311–2316. doi: 10.1002/eji.1830211004. [DOI] [PubMed] [Google Scholar]
  35. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]

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