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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Identification of DC21 as a Novel Target Gene Counter-regulated by IL-12 and IL-4

  • Kong, Kyoung-Ah (Department of Biological Science and Institute for Basic Science, SungKyunKwan University) ;
  • Jang, Ji-Young (Department of Biological Science and Institute for Basic Science, SungKyunKwan University) ;
  • Lee, Choong-Eun (Department of Biological Science and Institute for Basic Science, SungKyunKwan University)
  • Published : 2002.11.30
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Abstract

The Th1 vs. Th2 balance is critical for the maintenance of immune homeostasis. Therefore, the genes that are selectively-regulated by the Th1 and Th2 cytokines are likely to play an important role in the Th1 and Th2 immune responses. In order to search for and identify the novel target genes that are differentially regulated by the Th1/Th2 cytokines, the human PBMC mRNAs differentially expressed upon the stimulation with IL-4 or IL-12, were screened by employing the differential display-polymerase chain reaction. Among a number of clones selected, DC21 was identified as a novel target gene that is regulated by IL-4 and IL-12. The DC21 gene expression was up-regulated either by IL-4 or IL-12, yet counter-regulated by co-treatment with IL-4 and IL-12. DC21 is a dendritic cell protein with an unknown function. The sequence analysis and conserved-domain search revealed that it has two AU-rich motifs in the 3'UTR, which is a target site for the regulation of mRNA stability by cytokines, and that it belongs to the N-acetyltransferase family. The induction of DC21 by IL-12 peaked around 8-12 h, and lasted until 24 h. LY294002 and SB203580 significantly suppressed the IL-12-induced DC21 gene expression, which implies that PI3K and p38/JNK are involved in the IL-12 signal transduction pathway that leads to the DC21 expression. Furthermore, tissue blot data indicated that DC21 is highly expressed in tissues with specialized-resident macrophages, such as the lung, liver, kidney, and placenta. Together, these data suggest a possible role for DC21 in the differentiation and maturation of dendritic cells regulated by IL-4 and IL-12.

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References

  1. Adi, S., Wu, N-Y. and Rosenthal, S. M. (2001) Growth factor stimulated phosphorylation of Akt and $p70^{56k}$ is differentially inhibited by LY294002 and wortmannin, Endocrinology 142, 498-501. https://doi.org/10.1210/en.142.1.498
  2. Athie, M. V., Flotow, H., Hilyard, K. L. and Cantrell, D, A. (2000) IL-12 selectively regulates STAT4 via phosphatidyl inositol 3-kinase an Ras-independent signal transduction pathways. Eur. J, lmmunol. 30, 1425-1434, https://doi.org/10.1002/(SICI)1521-4141(200005)30:5<1425::AID-IMMU1425>3.0.CO;2-Q
  3. Avni. O., Lee. D., Macian, F., Szabo, S. J., Glimcher, L. H. and Rao, A. (2002) T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes, Nat. Immunol. 3, 643-651. https://doi.org/10.1038/nrg904
  4. Benn, C. S., Bendixen, M., Krause, T. G. and Olesen, A. B. (2002) Questionable co-existence of Th1- and Th2-related disease. J. Allergy Clin. lmmunol. 110, 328-329. https://doi.org/10.1067/mai.2002.126480
  5. Cao, H., Wolff, R, G., Meltzer, M. S. and Crawford, R. M. (1989) Differential regulation of class II MHC detenninants on macrophages by IFN-$\gamma$ and IL-4. J Immunol. 143, 3524-3529,
  6. Chen, C. Y., del Gatto-Konczak, F., Wu, Z. and Karin, M. (1998) Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 280, 1945-1949. https://doi.org/10.1126/science.280.5371.1945
  7. Cho, B. S., Yoon, S. R., Pyun, K. H., Jang, J. Y. and Lee, C. E. (1999) Up-regulation of interleukin-4 and CD23/Fc$\varepsilon$RII in childhood minimal change nephritic syndrome. Pediatr. Nephrol. 13, 199-204. https://doi.org/10.1007/s004670050592
  8. Constant, S. L. and Bottomly, L. (1997) Induction of Th1 and Th2 CD4+ T cell response: The alternative approaches. Ann, Rev. Immunol. 15, 297-321. https://doi.org/10.1146/annurev.immunol.15.1.297
  9. Denoroy, M. C. J., Yodoi, J. and Banchereau, J. (1990) Interleukin-4 and interferon-$\alpha$ and -$\gamma$ regulate Fc$\varepsilon$RII/CD23 mRNA expression on normal human B cells. Mol. lmmunol. 27, 129-132. https://doi.org/10.1016/0161-5890(90)90107-B
  10. Fields, P.E., Kim, S. T. and Flavell, R. A. (2002) Changes in histone acetylation at the IL-4 and IFN-$\gamma$ loci accompany Th1/Th2 differentiation. J. Immunol. 169, 647-650. https://doi.org/10.4049/jimmunol.169.2.647
  11. Fry, C. and Peterson, C. L. (2002) Unlocking the gates to gene expression. Science 295, 1847-1848. https://doi.org/10.1126/science.1070260
  12. Kammerer, U., Schoppet, M., McLellan, A. D., Kapp, M., Huppertz, H. L., Kampgen, E. and Deitl, J, (2000) Human deciduas contains potent immunostimulatory CD83(+) dendritic cells. Am. J. Pathol. 157, 159-169. https://doi.org/10.1016/S0002-9440(10)64527-0
  13. Koh, H, J., Park, H. H. and Lee, C. E. (2000) Regulation of IgE and type Il IgE receptor expression by insulin-like growth factor-1: Role of STAT6 and NF-$\kappa$B. J. Biochem, Mol. Biol. 33, 454-462
  14. Laman, J. D., Thompson, E. J. and Kappos, L. (1998) Balancing the Th1/Th2 concept in multiple sclerosis. lmmunol. Today 19, 489-490, https://doi.org/10.1016/S0167-5699(98)01320-6
  15. Lee, C. E., Yoon, S. R. and Pyun, K. H. (1993) Mechanism of interferon-$\gamma$ down-regulation of the interleukin 4-induced CD23/Fc$\varepsilon$RII expression in human B cells. Mol. Immunol. 30, 301-307. https://doi.org/10.1016/0161-5890(93)90058-J
  16. Lir, Y. J., Kadowsky, N., Rissan, M. C. and Soumelis, V. (2000) T cell activation and polarization by DC1 and DC2. Curr. Top. Microbiol. Immunol. 251, 149-159.
  17. Moser, M. and Murphy, K. M. (2000) Dendritic cell regulation of Th1-Th2 development. Nat. Immunol. 1, 199-205. https://doi.org/10.1038/79734
  18. Mosman, T. and Sad, S. (1996) The exp,mding universe of T-cell subsets: Th1, Th2 and more. Immunol, Today 17, 138-146. https://doi.org/10.1016/0167-5699(96)80606-2
  19. Olsson, T. (1995) Critical influences of cytokine orchestration on the outcome of myelin antigen-specific T cell autoimmunity in experimental autoimmune encephalomyelitis and sclerosis. Immnuol. Rev. 144, 245-268. https://doi.org/10.1111/j.1600-065X.1995.tb00072.x
  20. Park, J. -H., Lee, H. -Y., Roh, S, -C., Kim, H. -Y. and Yang, Y. -M. (2000) Screening of differentially expressed genes by desferrioxamine or ferric ammonium citrate treatment in HepG2 cells. J. Biochem. Mol, BioI. 33, 396-401.
  21. Ramech, L. E., Chen, C. S., and Candy, L. C. (1995) Phosphatidyl(3,4,5)P3 interacts with SH2 domains and modulating PI3kinase association with tyrosine phosphorylated protein. Cell 83, 821-830, https://doi.org/10.1016/0092-8674(95)90195-7
  22. Rissoan, M. C., Soumelis, V., Kadowaki, N., Grouard, G., Briere, F., de Waal Malefyt, R. and Liu, Y. J. (1999) Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183-1186. https://doi.org/10.1126/science.283.5405.1183
  23. Sallusto, F., Lenig, D., Mackay, C. R. and Lanzavecchia, A. (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 Iymphocytes. J. Exp. Med. 187, 875-883. https://doi.org/10.1084/jem.187.6.875
  24. Sato, M., Iwakabe, K., Kimura, S. and Nishimura, T. (1999) Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines. Immunol. Lett. 15, 63-68.
  25. Shaw, G. and Kanlen, R .(1986) A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659-667. https://doi.org/10.1016/0092-8674(86)90341-7
  26. Snapper, C. M. and Paul, W. E. (1987) Interferon-$\gamma$ and B cell stimulatory factor reciprocally regulate Ig isotype production. Science 236, 944-948. https://doi.org/10.1126/science.3107127
  27. So, E. Y., Jang, J. Y. and Lee, C. E. (2001) Cross-talk between Jak/STAT lmd Ras/MAPK pathways for the IL-4-mediated Th cell survival. J. Biochem. MoI. BioI. 34, 578-583.
  28. So, E. Y., Park, H. H. and Lee, C. E. (2000) IFN-$\gamma$ and IFN-$\alpha$ post-transcriptionally down-regulate the IL-4-induced IL-4 receptnr gene expression. J. lmmunol. 165, 5472-5479. https://doi.org/10.4049/jimmunol.165.10.5472
  29. Song, J. -H., Park, H. -J., Park, H. -H., Kim, S. -H., Han, M. -Y. and Lee, C. E. (2001) Role of STAT3 as a molecular adaptor in cell growth signaling: Interaction with Ras and other STAT proteins. J. Biochem. Mol. BioI. 34, 484-488,
  30. Soutoglou, E., Vollet, B., Vaxillaire, M., Yaniv, M., Pontoglio, M. and Taliandis, I. (2001) Transcription factor-dependent regulation of CBP and P/CAF histone acetyltransferase activity. EMBO J. 17, 1984-1992.
  31. Stoher, D., Schirmbeck, R. and Reimann, J. (2001) IL-12/IL-18- dependent IFN-gamma release by murine dendritic cells. J. Immunol. 167, 957-965. https://doi.org/10.4049/jimmunol.167.2.957
  32. Viney, J. L. (1999) Dendritic cell subsets: the ultimate T cell differentiation decision makers? Gut. 45, 640-641. https://doi.org/10.1136/gut.45.5.640
  33. Yang, D. D., Conze, D., Whitmarch, A. H., Barrett, T., Davis, R. H., Rincon, M. and Flavell, R. A. (1998) Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. Immunity 9, 575-585. https://doi.org/10.1016/S1074-7613(00)80640-8
  34. Xu, X., Yang, Y., Gao, G., Xiao, H., Chen, Z. and Han, Z. (2001) GenBank accession #AF251292.
  35. Zhang, S. and Kaplan, M. H. (2000) The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-$\gamma$ expression. J. Immunol. 165, 1374-1380. https://doi.org/10.4049/jimmunol.165.3.1374

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