Advertisement

Molecules and Cells

, Volume 31, Issue 2, pp 141–149 | Cite as

Regulation of mouse 4-1BB expression: Multiple promoter usages and a splice variant

  • Jung D. Kim
  • Chang H. Kim
  • Byoung S. KwonEmail author
Article

Abstract

The expression of 4-1BB has been known to be dependent on T cell activation. Recent studies have, however, revealed that 4-1BB expression is not restricted to T cells. We sought to determine the molecular basis for the differential gene expression. Here we report the expression pattern of two mouse 4-1BB transcripts, type I and type II. Whereas the type I transcript was specifically expressed on immune organ as previously reported, the type II transcript was ubiquitously expressed in tissues and various cell lines. However, both type I and type II transcript were highly induced on activated T cells. Primer extension assay of the two 4-1BB transcripts suggested that mouse 4-1BB had more than two transcripts. Using luciferase assay we have identified three promoter regions (PI, PII and PIII), which located on upstream region of second exon 1, first exon 1, and exon 2, respectively. In particular, the type I transcript was preferentially induced when naïve T cells are stimulated by anti-CD3 monoclonal antibody (mAb) since NF-κB specifically binds to the putative NF-κB element of PI. We have also shown that a splice variant, in which the transmembrane domain was deleted, could inhibit 4-1BB signaling. The splicing variant was highly induced by TCR stimulation. Our results reveal 4-1BB also has a negative regulation system through soluble 4-1BB produced from a splice variant induced under activation conditions.

Keywords

4-1BB NF-κB promoter splice variant 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alderson, M.R., Smith, C.A., Tough, T.W., Davis-Smith, T., Armitage, R.J., Falk, B., Roux, E., Baker, E., Sutherland, G.R., and Din, W.S. (1994). Molecular and biological characterization of human 4-1BB and its ligand. Eur. J. Immunol. 24, 2219–2227.PubMedCrossRefGoogle Scholar
  2. Boussaud, V., Soler, P., Moreau, J., Goodwin, R.G., and Hance, A.J. (1998). Expression of three members of the TNF-R family of receptors (4-1BB, lymphotoxin-beta receptor, and Fas) in human lung. Eur. Respir. J. 12, 926–931.PubMedCrossRefGoogle Scholar
  3. Broll, K., Richter, G., Pauly, S., Hofstaedter, F., and Schwarz, H. (2001). CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am. J. Clin. Pathol. 115, 543–549.PubMedCrossRefGoogle Scholar
  4. Cascino, I., Fiucci, G., Papoff, G., and Ruberti, G. (1995). Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J. Immunol. 154, 2706–2713.PubMedGoogle Scholar
  5. Cascino, I., Papoff, G., De Maria, R., Testi, R., and Ruberti, G. (1996). Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling domain protects tumor cells from Fas-mediated apoptosis. J. Immunol. 156, 13–17.PubMedGoogle Scholar
  6. Cheng, J., Zhou, T., Liu, C., Shapiro, J.P., Brauer, M.J., Kiefer, M.C., Barr, P.J., and Mountz, J.D. (1994). Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263, 1759–1762.PubMedCrossRefGoogle Scholar
  7. Christophi, G.P., Isackson, P.J., Blaber, S., Blaber, M., Rodriguez, M., and Scarisbrick, I.A. (2004). Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease. J. Neurochem. 91, 1439–1449.PubMedCrossRefGoogle Scholar
  8. DeBenedette, M.A., Chu, N.R., Pollok, K.E., Hurtado, J., Wade, W.F., Kwon, B.S., and Watts, T.H. (1995). Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J. Exp. Med. 181, 985–992.PubMedCrossRefGoogle Scholar
  9. DeBenedette, M.A., Shahinian, A., Mak, T.W., and Watts, T.H. (1997). Costimulation of CD28-T lymphocytes by 4-1BB ligand. J. Immunol. 158, 551–559.PubMedGoogle Scholar
  10. Dignam, J.D., Lebovitz, R.M., and Roeder, R.G. (1983). Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11, 1475–1489.PubMedCrossRefGoogle Scholar
  11. Furtner, M., Straub, R.H., Kruger, S., and Schwarz, H. (2005). Levels of soluble CD137 are enhanced in sera of leukemia and lymphoma patients and are strongly associated with chronic lymphocytic leukemia. Leukemia 19, 883–885.PubMedCrossRefGoogle Scholar
  12. Futagawa, T., Akiba, H., Kodama, T., Takeda, K., Hosoda, Y., Yagita, H., and Okumura, K. (2002). Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int. Immunol. 14, 275–286.PubMedCrossRefGoogle Scholar
  13. Garni-Wagner, B.A., Lee, Z.H., Kim, Y.J., Wilde, C., Kang, C.Y., and Kwon, B.S. (1996). 4-1BB is expressed on CD45RAhiROhi transitional T cell in humans. Cell. Immunol. 169, 91–98.PubMedCrossRefGoogle Scholar
  14. Goodwin, R.G., Din, W.S., Davis-Smith, T., Anderson, D.M., Gimpel, S.D., Sato, T.A., Maliszewski, C.R., Brannan, C.I., Copeland, N.G., Jenkins, N.A., et al. (1993). Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur. J. Immunol. 23, 2631–2641.PubMedCrossRefGoogle Scholar
  15. Hai, M., Bidichandani, S.I., and Patel, P.I. (2001). Identification of a positive regulatory element in the myelin-specific promoter of the PMP22 gene. J. Neurosci. Res. 65, 508–519.PubMedCrossRefGoogle Scholar
  16. Heinisch, I.V., Daigle, I., Knopfli, B., and Simon, H.U. (2000). CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils. Eur. J. Immunol. 30, 3441–3446.PubMedCrossRefGoogle Scholar
  17. Heinisch, I.V., Bizer, C., Volgger, W., and Simon, H.U. (2001). Functional CD137 receptors are expressed by eosinophils from patients with IgE-mediated allergic responses but not by eosinophils from patients with non-IgE-mediated eosinophilic disorders. J. Allergy Clin. Immunol. 108, 21–28.PubMedCrossRefGoogle Scholar
  18. Hurtado, J.C., Kim, S.H., Pollok, K.E., Lee, Z.H., and Kwon, B.S. (1995). Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28. J. Immunol. 155, 3360–3367.PubMedGoogle Scholar
  19. Hurtado, J.C., Kim, Y.J., and Kwon, B.S. (1997). Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. J. Immunol. 158, 2600–2609.PubMedGoogle Scholar
  20. Jian, J.L., Zhu, C.S., Xu, Z.W., Ouyang, W.M., Ma, D.C., Zhang, Y., Chen, L.J., Yang, A.G., and Jin, B.Q. (2006). Identification and characterization of the CD226 gene promoter. J. Biol. Chem. 281, 28731–28736.PubMedCrossRefGoogle Scholar
  21. Jung, H.W., Choi, S.W., Choi, J.I., and Kwon, B.S. (2004). Serum concentrations of soluble 4-1BB and 4-1BB ligand correlated with the disease severity in rheumatoid arthritis. Exp. Mol. Med. 36, 13–22.PubMedGoogle Scholar
  22. Kim, K.M., Kim, H.W., Kim, J.O., Baek, K.M., Kim, J.G., and Kang, C.Y. (2002). Induction of 4-1BB (CD137) expression by DNA damaging agents in human T lymphocytes. Immunology 107, 472–479.PubMedCrossRefGoogle Scholar
  23. Kim, J.O., Kim, H.W., Baek, K.M., and Kang, C.Y. (2003). NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells. FEBS Lett. 541, 163–170.PubMedCrossRefGoogle Scholar
  24. Kohno, T., Brewer, M.T., Baker, S.L., Schwartz, P.E., King, M.W., Hale, K.K., Squires, C.H., Thompson, R.C., and Vannice, J.L. (1990). A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc. Natl. Acad. Sci. USA 87, 8331–8335.PubMedCrossRefGoogle Scholar
  25. Kwon, B.S., and Weissman, S.M. (1989). cDNA sequences of two inducible T-cell genes. Proc. Natl. Acad. Sci. USA 86, 1963–1967.PubMedCrossRefGoogle Scholar
  26. Kwon, B.S., Kim, G.S., Prystowsky, M.B., Lancki, D.W., Sabath, D.E., Pan, J.L., and Weissman, S.M. (1987). Isolation and initial characterization of multiple species of T-lymphocyte subset cDNA clones. Proc. Natl. Acad. Sci. USA 84, 2896–2900.PubMedCrossRefGoogle Scholar
  27. Kwon, B.S., Kestler, D.P., Eshhar, Z., Oh, K.O., and Wakulchik, M. (1989). Expression characteristics of two potential T cell mediator genes. Cell. Immunol. 121, 414–422.PubMedCrossRefGoogle Scholar
  28. Kwon, B.S., Kozak, C.A., Kim, K.K., and Pickard, R.T. (1994). Genomic organization and chromosomal localization of the T-cell antigen 4-1BB. J. Immunol. 152, 2256–2262.PubMedGoogle Scholar
  29. Kwon, B., Moon, C.H., Kang, S., Seo, S.K., and Kwon, B.S. (2000). 4-1BB: still in the midst of darkness. Mol. Cells 10, 119–126.PubMedCrossRefGoogle Scholar
  30. Langstein, J., and Schwarz, H. (1999). Identification of CD137 as a potent monocyte survival factor. J. Leukoc. Biol. 65, 829–833.PubMedGoogle Scholar
  31. Langstein, J., Michel, J., Fritsche, J., Kreutz, M., Andreesen, R., and Schwarz, H. (1998). CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. J. Immunol. 160, 2488–2494.PubMedGoogle Scholar
  32. Langstein, J., Michel, J., and Schwarz, H. (1999). CD137 induces proliferation and endomitosis in monocytes. Blood 94, 3161–3168.PubMedGoogle Scholar
  33. Lee, S.C., Ju, S.A., Pack, H.N., Heo, S.K., Suh, J.H., Park, S.M., Choi, B.K., Kwon, B.S., and Kim, B.S. (2005). 4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection. Infect. Immun. 73, 5144–5151.PubMedCrossRefGoogle Scholar
  34. Lotz, M., Setareh, M., von Kempis, J., and Schwarz, H. (1996). The nerve growth factor/tumor necrosis factor receptor family. J. Leukoc. Biol. 60, 1–7.PubMedGoogle Scholar
  35. McHugh, R.S., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M., and Byrne, M.C. (2002). CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323.PubMedCrossRefGoogle Scholar
  36. Michel, J., Langstein, J., Hofstadter, F., and Schwarz, H. (1998). A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur. J. Immunol. 28, 290–295.PubMedCrossRefGoogle Scholar
  37. Nocentini, G., Ronchetti, S., Bartoli, A., Spinicelli, S., Delfino, D., Brunetti, L., Migliorati, G., and Riccardi, C. (2000). Identification of three novel mRNA splice variants of GITR. Cell Death Differ. 7, 408–410.PubMedCrossRefGoogle Scholar
  38. Pizzolo, G., Vinante, F., Chilosi, M., Dallenbach, F., Josimovic-Alasevic, O., Diamantstein, T., and Stein, H. (1990). Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin’s disease: relationship with disease activity and clinical stage. Br. J. Haematol. 75, 282–284.PubMedCrossRefGoogle Scholar
  39. Pollok, K.E., Kim, Y.J., Zhou, Z., Hurtado, J., Kim, K.K., Pickard, R.T., and Kwon, B.S. (1993). Inducible T cell antigen 4-1BB. Analysis of expression and function. J. Immunol. 150, 771–781.PubMedGoogle Scholar
  40. Pollok, K.E., Kim, Y.J., Hurtado, J., Zhou, Z., Kim, K.K., and Kwon, B.S. (1994). 4-1BB T-cell antigen binds to mature B cells and macrophages, and costimulates anti-mu-primed splenic B cells. Eur. J. Immunol. 24, 367–374.PubMedCrossRefGoogle Scholar
  41. Pollok, K.E., Kim, S.H., and Kwon, B.S. (1995). Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4. Eur. J. Immunol. 25, 488–494.PubMedCrossRefGoogle Scholar
  42. Reali, C., Curto, M., Sogos, V., Scintu, F., Pauly, S., Schwarz, H., and Gremo, F. (2003). Expression of CD137 and its ligand in human neurons, astrocytes, and microglia: modulation by FGF-2. J. Neurosci. Res. 74, 67–73.PubMedCrossRefGoogle Scholar
  43. Reynolds, P.J., Lesley, J., Trotter, J., Schulte, R., Hyman, R., and Sefton, B.M. (1990). Changes in the relative abundance of type I and type II lck mRNA transcripts suggest differential promoter usage during T-cell development. Mol. Cell. Biol. 10, 4266–4270.PubMedGoogle Scholar
  44. Saoulli, K., Lee, S.Y., Cannons, J.L., Yeh, W.C., Santana, A., Goldstein, M.D., Bangia, N., DeBenedette, M.A., Mak, T.W., Choi, Y., et al. (1998). CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J. Exp. Med. 187, 1849–1862.PubMedCrossRefGoogle Scholar
  45. Schwarz, H., Valbracht, J., Tuckwell, J., von Kempis, J., and Lotz, M. (1995). ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. Blood 85, 1043–1052.PubMedGoogle Scholar
  46. Schwarz, H., Blanco, F.J., von Kempis, J., Valbracht, J., and Lotz, M. (1996). ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival. Blood 87, 2839–2845.PubMedGoogle Scholar
  47. Seko, Y., Sugishita, K., Sato, O., Takagi, A., Tada, Y., Matsuo, H., Yagita, H., Okumura, K., and Nagai, R. (2004). Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu’s arteritis. J. Vasc. Res. 41, 84–90.PubMedCrossRefGoogle Scholar
  48. Setareh, M., Schwarz, H., and Lotz, M. (1995). A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF/TNF receptor family. Gene 164, 311–315.PubMedCrossRefGoogle Scholar
  49. Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.T., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., et al. (1997). 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55.PubMedCrossRefGoogle Scholar
  50. Takahashi, C., Mittler, R.S., and Vella, A.T. (1999). Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J. Immunol. 162, 5037–5040.PubMedGoogle Scholar
  51. Tao, L., Dong, Z., Zannis-Hadjopoulos, M., and Price, G.B. (2001). Immortalization of human WI38 cells is associated with differential activation of the c-myc origins. J. Cell. Biochem. 82, 522–534.PubMedCrossRefGoogle Scholar
  52. Watts, T.H. (2005). TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68.PubMedCrossRefGoogle Scholar
  53. Wilcox, R.A., Chapoval, A.I., Gorski, K.S., Otsuji, M., Shin, T., Flies, D.B., Tamada, K., Mittler, R.S., Tsuchiya, H., Pardoll, D.M., et al. (2002). Cutting edge: Expression of functional CD137 receptor by dendritic cells. J. Immunol. 168, 4262–4267.PubMedGoogle Scholar
  54. Xiao, Z.S., Simpson, L.G., and Quarles, L.D. (2003). IRES-dependent translational control of Cbfa1/Runx2 expression. J. Cell. Biochem. 88, 493–505.PubMedCrossRefGoogle Scholar
  55. Yamada, A., Takaki, S., Hayashi, F., Georgopoulos, K., Perlmutter, R.M., and Takatsu, K. (2001). Identification and characterization of a transcriptional regulator for the lck proximal promoter. J. Biol. Chem. 276, 18082–18089.PubMedCrossRefGoogle Scholar
  56. Zupan, A.A., Osborne, P.A., Smith, C.E., Siegel, N.R., Leimgruber, R.M., and Johnson, E.M., Jr. (1989). Identification, purification, and characterization of truncated forms of the human nerve growth factor receptor. J. Biol. Chem. 264, 11714–11720.PubMedGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2011

Authors and Affiliations

  1. 1.Biomedical Research Center, Ulsan University Hospital, College of MedicineUniversity of UlsanUlsanKorea
  2. 2.Division of Cell and Immunobiology and R&D Center for Cancer TherapeuticsNational Cancer CenterIlsanKorea
  3. 3.Department of medicineTulane UniversityNew OrleansUSA

Personalised recommendations