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. 1985 Oct;56(2):321–327.

Activation and proliferation signals in mouse B cells. VII. Calcium ionophores are non-mitogenic polyclonal B-cell activators.

G G Klaus, M K Bijsterbosch, M Holman
PMCID: PMC1453682  PMID: 2414214

Abstract

Calcium ionophores cause polyclonal proliferation of lymphocytes from man, rabbit and pig, but are not mitogenic for mouse T or B lymphocytes. We show here that two Ca2+ ionophores (A23187 and ionomycin) nonetheless activate a substantial proportion of mouse B lymphocytes at concentrations which effectively inhibit DNA synthesis induced by conventional mitogens, such as anti-immunoglobulin antibodies. Activation of B cells was detected by (i) increased expression of Ia antigen after 24 hr culture with ionophores, and (ii) the accelerated onset of DNA synthesis in B cells primed with ionophores for 24 hr, washed and then rechallenged with anti-Ig. Unlike anti-Ig, the ionophores did not induce either the breakdown of inositol phospholipids, or RNA synthesis in B cells. Finally, activation of B cells by ionophores is highly susceptible to inhibition by cyclosporine. These results therefore suggest that elevation of intracellular Ca2+ induced by these ionophores is sufficient to cause B cells to leave Go, but not to enter the G1 phase of the cell cycle. Clearly, additional signals are required for B cells to progress further into cycle and eventually become committed to DNA synthesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alford R. H. Metal cation requirements for phytohemagglutinin-induced transformation of human peripheral blood lymphocytes. J Immunol. 1970 Mar;104(3):698–703. [PubMed] [Google Scholar]
  2. Beretta A., Gullberg M., Larsson E. L., Möller G. Ionophore A23-187 induces responses to TCGF in mouse lymphocytes. Ann Immunol (Paris) 1984 May-Jun;135C(3):365–373. doi: 10.1016/s0769-2625(84)80966-6. [DOI] [PubMed] [Google Scholar]
  3. Berridge M. J. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984 Jun 1;220(2):345–360. doi: 10.1042/bj2200345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coggeshall K. M., Cambier J. C. B cell activation. VIII. Membrane immunoglobulins transduce signals via activation of phosphatidylinositol hydrolysis. J Immunol. 1984 Dec;133(6):3382–3386. [PubMed] [Google Scholar]
  5. Dongworth D. W., Klaus G. G. Effects of cyclosporin A on the immune system of the mouse. I. Evidence for a direct selective effect of cyclosporin A on B cells responding to anti-immunoglobulin antibodies. Eur J Immunol. 1982 Dec;12(12):1018–1022. doi: 10.1002/eji.1830121207. [DOI] [PubMed] [Google Scholar]
  6. Freedman M. H., Khan N. R., Trew-Marshall B. J., Cupples C. G., Mély-Goubert B. Early biochemical events in lymphocyte activation. II. Selectivity of A23187 for T lymphocytes and the use of an apolar fluorescent probe (1,6-diphenyl-1,3,5-hexatriene) to monitor ionophore- and lectin-induced lymphocyte activation. Cell Immunol. 1981 Feb;58(1):134–146. doi: 10.1016/0008-8749(81)90155-6. [DOI] [PubMed] [Google Scholar]
  7. Hawrylowicz C. M., Keeler K. D., Klaus G. G. Activation and proliferation signals in mouse B cells. I. A comparison of the capacity of anti-Ig antibodies or phorbol myristic acetate to activate B cells from CBA/N or normal mice into G1. Eur J Immunol. 1984 Mar;14(3):244–250. doi: 10.1002/eji.1830140308. [DOI] [PubMed] [Google Scholar]
  8. Hawrylowicz C. M., Klaus G. G. Activation and proliferation signals in mouse B cells. IV. Concanavalin A stimulates B cells to leave G0, but not to proliferate. Immunology. 1984 Dec;53(4):703–711. [PMC free article] [PubMed] [Google Scholar]
  9. Hovi T., Allison A. C., Williams S. C. Proliferation of human peripheral blood lymphocytes induced by A23187, a streptomyces antibiotic. Exp Cell Res. 1976 Jan;97:92–100. doi: 10.1016/0014-4827(76)90658-3. [DOI] [PubMed] [Google Scholar]
  10. Kay J. E., Benzie C. R., Borghetti A. F. Effect of cyclosporin A on lymphocyte activation by the calcium ionophore A23187. Immunology. 1983 Nov;50(3):441–446. [PMC free article] [PubMed] [Google Scholar]
  11. Klaus G. G., Hawrylowicz C. M. Activation and proliferation signals in mouse B cells. II. Evidence for activation (G0 to G1) signals differing in sensitivity to cyclosporine. Eur J Immunol. 1984 Mar;14(3):250–254. doi: 10.1002/eji.1830140309. [DOI] [PubMed] [Google Scholar]
  12. Klaus G. G., Hawrylowicz C. M., Holman M., Keeler K. D. Activation and proliferation signals in mouse B cells. III. Intact (IGG) anti-immunoglobulin antibodies activate B cells but inhibit induction of DNA synthesis. Immunology. 1984 Dec;53(4):693–701. [PMC free article] [PubMed] [Google Scholar]
  13. Lichtman A. H., Segel G. B., Lichtman M. A. The role of calcium in lymphocyte proliferation. (An interpretive review). Blood. 1983 Mar;61(3):413–422. [PubMed] [Google Scholar]
  14. Luckasen J. R., White J. G., Kersey J. H. Mitogenic properties of a calcium ionophore, A23187. Proc Natl Acad Sci U S A. 1974 Dec;71(12):5088–5090. doi: 10.1073/pnas.71.12.5088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Maino V. C., Green N. M., Crumpton M. J. The role of calcium ions in initiating transformation of lymphocytes. Nature. 1974 Sep 27;251(5473):324–327. doi: 10.1038/251324b0. [DOI] [PubMed] [Google Scholar]
  16. Metcalfe S. Cyclosporine does not prevent cytoplasmic calcium changes associated with lymphocyte activation. Transplantation. 1984 Aug;38(2):161–164. doi: 10.1097/00007890-198408000-00014. [DOI] [PubMed] [Google Scholar]
  17. Mond J. J., Seghal E., Kung J., Finkelman F. D. Increased expression of I-region-associated antigen (Ia) on B cells after cross-linking of surface immunoglobulin. J Immunol. 1981 Sep;127(3):881–888. [PubMed] [Google Scholar]
  18. Monroe J. G., Cambier J. C. B cell activation. III. B cell plasma membrane depolarization and hyper-Ia antigen expression induced by receptor immunoglobulin cross-linking are coupled. J Exp Med. 1983 Nov 1;158(5):1589–1599. doi: 10.1084/jem.158.5.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Monroe J. G., Niedel J. E., Cambier J. C. B cell activation. IV. Induction of cell membrane depolarization and hyper-I-A expression by phorbol diesters suggests a role for protein kinase C in murine B lymphocyte activation. J Immunol. 1984 Mar;132(3):1472–1478. [PubMed] [Google Scholar]
  20. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  21. Resch K., Bouillon D., Gemsa D. The activation of lymphocytes by the ionophore A 23 187. J Immunol. 1978 May;120(5):1514–1520. [PubMed] [Google Scholar]
  22. Rosenstreich D. L., Blumenthal R. Ionophorous activity and murine B lymphocyte mitogens. J Immunol. 1977 Jan;118(1):129–136. [PubMed] [Google Scholar]
  23. Taylor M. V., Metcalfe J. C., Hesketh T. R., Smith G. A., Moore J. P. Mitogens increase phosphorylation of phosphoinositides in thymocytes. 1984 Nov 29-Dec 5Nature. 312(5993):462–465. doi: 10.1038/312462a0. [DOI] [PubMed] [Google Scholar]
  24. Truneh A., Albert F., Golstein P., Schmitt-Verhulst A. M. Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature. 1985 Jan 24;313(6000):318–320. doi: 10.1038/313318a0. [DOI] [PubMed] [Google Scholar]
  25. Whitney R. B., Sutherland R. M. Requirement for calcium ions in lymphocyte transformation stimulated by phytohemagglutinin. J Cell Physiol. 1972 Dec;80(3):329–337. doi: 10.1002/jcp.1040800303. [DOI] [PubMed] [Google Scholar]

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