Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Dec;87(23):9353–9357. doi: 10.1073/pnas.87.23.9353

cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells.

T J Novak 1, E V Rothenberg 1
PMCID: PMC55163  PMID: 2174560

Abstract

In this report, we explore the nature of the inductive stimuli leading to expression of the divergently regulated lymphokines interleukin 2 (IL-2) and interleukin 4 (IL-4). Elevation of cAMP levels blocks IL-2 induction while sparing IL-4 induction. These effects are gene-specific, not cell-specific, and can be observed in the same cells. Transient transfection experiments using murine IL-2 regulatory sequences to drive expression of a reporter gene show at least part of the inhibition to act at the transcriptional level. The possible biological significance of these results is indicated by the observation that representative type 2 helper T-cell lines maintain significantly higher levels of cAMP per cell than a type 1 helper T-cell line. Fresh splenic CD4+ T cells, which preferentially make IL-2, have particularly low levels of cAMP per cell and a low capacity to elevate cAMP in response to forskolin. However, their response to forskolin increases significantly after several days of stimulation. These results suggest a potential link between differential cAMP regulation and the divergence of memory T cells into effector subsets.

Full text

PDF
9353

Images in this article

9354Image
on p.9354
9354Image
on p.9354
9354Image
on p.9354

Selected References

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

  1. Brown M. A., Pierce J. H., Watson C. J., Falco J., Ihle J. N., Paul W. E. B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells. Cell. 1987 Aug 28;50(5):809–818. doi: 10.1016/0092-8674(87)90339-4. [DOI] [PubMed] [Google Scholar]
  2. Chouaib S., Welte K., Mertelsmann R., Dupont B. Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression. J Immunol. 1985 Aug;135(2):1172–1179. [PubMed] [Google Scholar]
  3. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  4. Daynes R. A., Araneo B. A. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur J Immunol. 1989 Dec;19(12):2319–2325. doi: 10.1002/eji.1830191221. [DOI] [PubMed] [Google Scholar]
  5. Farrar J. J., Fuller-Farrar J., Simon P. L., Hilfiker M. L., Stadler B. M., Farrar W. L. Thymoma production of T cell growth factor (Interleukin 2). J Immunol. 1980 Dec;125(6):2555–2558. [PubMed] [Google Scholar]
  6. Favaloro J., Treisman R., Kamen R. Transcription maps of polyoma virus-specific RNA: analysis by two-dimensional nuclease S1 gel mapping. Methods Enzymol. 1980;65(1):718–749. doi: 10.1016/s0076-6879(80)65070-8. [DOI] [PubMed] [Google Scholar]
  7. Firestein G. S., Roeder W. D., Laxer J. A., Townsend K. S., Weaver C. T., Hom J. T., Linton J., Torbett B. E., Glasebrook A. L. A new murine CD4+ T cell subset with an unrestricted cytokine profile. J Immunol. 1989 Jul 15;143(2):518–525. [PubMed] [Google Scholar]
  8. Gajewski T. F., Schell S. R., Fitch F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J Immunol. 1990 Jun 1;144(11):4110–4120. [PubMed] [Google Scholar]
  9. Gilbert K. M., Hoang K. D., Weigle W. O. Th1 and Th2 clones differ in their response to a tolerogenic signal. J Immunol. 1990 Mar 15;144(6):2063–2071. [PubMed] [Google Scholar]
  10. Greenberger J. S., Sakakeeny M. A., Humphries R. K., Eaves C. J., Eckner R. J. Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines. Proc Natl Acad Sci U S A. 1983 May;80(10):2931–2935. doi: 10.1073/pnas.80.10.2931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Groux H., Huet S., Valentin H., Pham D., Bernard A. Suppressor effects and cyclic AMP accumulation by the CD29 molecule of CD4+ lymphocytes. Nature. 1989 May 11;339(6220):152–154. doi: 10.1038/339152a0. [DOI] [PubMed] [Google Scholar]
  12. Hayakawa K., Hardy R. R. Phenotypic and functional alteration of CD4+ T cells after antigen stimulation. Resolution of two populations of memory T cells that both secrete interleukin 4. J Exp Med. 1989 Jun 1;169(6):2245–2250. doi: 10.1084/jem.169.6.2245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Holzmann B., McIntyre B. W., Weissman I. L. Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Cell. 1989 Jan 13;56(1):37–46. doi: 10.1016/0092-8674(89)90981-1. [DOI] [PubMed] [Google Scholar]
  14. Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kaye J., Gillis S., Mizel S. B., Shevach E. M., Malek T. R., Dinarello C. A., Lachman L. B., Janeway C. A., Jr Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol. 1984 Sep;133(3):1339–1345. [PubMed] [Google Scholar]
  16. Killar L., MacDonald G., West J., Woods A., Bottomly K. Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells. J Immunol. 1987 Mar 15;138(6):1674–1679. [PubMed] [Google Scholar]
  17. Kim D. K., Lancki D. W., Hui F. H., Fitch F. W. Protein kinase C-dependent and -independent mechanisms of cloned murine T cell proliferation. The role of protein kinase C translocation and protein kinase C activity. J Immunol. 1989 Jan 15;142(2):616–622. [PubMed] [Google Scholar]
  18. Lerner A., Jacobson B., Miller R. A. Cyclic AMP concentrations modulate both calcium flux and hydrolysis of phosphatidylinositol phosphates in mouse T lymphocytes. J Immunol. 1988 Feb 1;140(3):936–940. [PubMed] [Google Scholar]
  19. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  20. Lorenz R. G., Allen P. M. Thymic cortical epithelial cells lack full capacity for antigen presentation. Nature. 1989 Aug 17;340(6234):557–559. doi: 10.1038/340557a0. [DOI] [PubMed] [Google Scholar]
  21. Mary D., Aussel C., Ferrua B., Fehlmann M. Regulation of interleukin 2 synthesis by cAMP in human T cells. J Immunol. 1987 Aug 15;139(4):1179–1184. [PubMed] [Google Scholar]
  22. McGuire K. L., Rothenberg E. V. Inducibility of interleukin-2 RNA expression in individual mature and immature T lymphocytes. EMBO J. 1987 Apr;6(4):939–946. doi: 10.1002/j.1460-2075.1987.tb04842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McGuire K. L., Yang J. A., Rothenberg E. V. Influence of activating stimulus on functional phenotype: interleukin 2 mRNA accumulation differentially induced by ionophore and receptor ligands in subsets of murine T cells. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6503–6507. doi: 10.1073/pnas.85.17.6503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morimoto C., Letvin N. L., Boyd A. W., Hagan M., Brown H. M., Kornacki M. M., Schlossman S. F. The isolation and characterization of the human helper inducer T cell subset. J Immunol. 1985 Jun;134(6):3762–3769. [PubMed] [Google Scholar]
  25. Morimoto C., Letvin N. L., Distaso J. A., Aldrich W. R., Schlossman S. F. The isolation and characterization of the human suppressor inducer T cell subset. J Immunol. 1985 Mar;134(3):1508–1515. [PubMed] [Google Scholar]
  26. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  27. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  28. Muñoz E., Zubiaga A. M., Merrow M., Sauter N. P., Huber B. T. Cholera toxin discriminates between T helper 1 and 2 cells in T cell receptor-mediated activation: role of cAMP in T cell proliferation. J Exp Med. 1990 Jul 1;172(1):95–103. doi: 10.1084/jem.172.1.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Novak T. J., White P. M., Rothenberg E. V. Regulatory anatomy of the murine interleukin-2 gene. Nucleic Acids Res. 1990 Aug 11;18(15):4523–4533. doi: 10.1093/nar/18.15.4523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. O'Shea J. J., Urdahl K. B., Luong H. T., Chused T. M., Samelson L. E., Klausner R. D. Aluminum fluoride induces phosphatidylinositol turnover, elevation of cytoplasmic free calcium, and phosphorylation of the T cell antigen receptor in murine T cells. J Immunol. 1987 Nov 15;139(10):3463–3469. [PubMed] [Google Scholar]
  31. Plaut M., Pierce J. H., Watson C. J., Hanley-Hyde J., Nordan R. P., Paul W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores. Nature. 1989 May 4;339(6219):64–67. doi: 10.1038/339064a0. [DOI] [PubMed] [Google Scholar]
  32. Powers G. D., Abbas A. K., Miller R. A. Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations. J Immunol. 1988 May 15;140(10):3352–3357. [PubMed] [Google Scholar]
  33. Rothenberg E. V., Diamond R. A., Pepper K. A., Yang J. A. IL-2 gene inducibility in T cells before T cell receptor expression. Changes in signaling pathways and gene expression requirements during intrathymic maturation. J Immunol. 1990 Mar 1;144(5):1614–1624. [PubMed] [Google Scholar]
  34. Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
  35. Serra H. M., Krowka J. F., Ledbetter J. A., Pilarski L. M. Loss of CD45R (Lp220) represents a post-thymic T cell differentiation event. J Immunol. 1988 Mar 1;140(5):1435–1441. [PubMed] [Google Scholar]
  36. Shaw J., Meerovitch K., Bleackley R. C., Paetkau V. Mechanisms regulating the level of IL-2 mRNA in T lymphocytes. J Immunol. 1988 Apr 1;140(7):2243–2248. [PubMed] [Google Scholar]
  37. Swain S. L., McKenzie D. T., Dutton R. W., Tonkonogy S. L., English M. The role of IL4 and IL5: characterization of a distinct helper T cell subset that makes IL4 and IL5 (Th2) and requires priming before induction of lymphokine secretion. Immunol Rev. 1988 Feb;102:77–105. doi: 10.1111/j.1600-065x.1988.tb00742.x. [DOI] [PubMed] [Google Scholar]
  38. Swain S. L., Weinberg A. D., English M. CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro. J Immunol. 1990 Mar 1;144(5):1788–1799. [PubMed] [Google Scholar]
  39. Tony H. P., Phillips N. E., Parker D. C. Role of membrane immunoglobulin (Ig) crosslinking in membrane Ig-mediated, major histocompatibility-restricted T cell-B cell cooperation. J Exp Med. 1985 Nov 1;162(5):1695–1708. doi: 10.1084/jem.162.5.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weiss A., Stobo J. D. Requirement for the coexpression of T3 and the T cell antigen receptor on a malignant human T cell line. J Exp Med. 1984 Nov 1;160(5):1284–1299. doi: 10.1084/jem.160.5.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Williams M. E., Lichtman A. H., Abbas A. K. Anti-CD3 antibody induces unresponsiveness to IL-2 in Th1 clones but not in Th2 clones. J Immunol. 1990 Feb 15;144(4):1208–1214. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES