Skip to main content
Log in

The influence of ADAR1’s regulation on lymphocyte cell function during rejection

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The RNA editing adenosine deaminase gene (ADAR1) expression is wide-spread in lymphocytes. We explore the mechanism of ADAR1 regulation on the function of T primary lymphocytes when rejection occurs by knock-down the expression of ADAR1 in mouse T primary lymphocytes in mixed lymphocyte cultures. The changes of cell proliferation, the expression of ADAR1 and the cell cycle related genes cyclin D1 and A1, cell cycle and apoptosis analysis and mouse gene expression profiles was evaluated. We found that treatment with ADAR1-specific siRNA inhibited allogenic antigen stimulated T cell proliferation, arrested T cell cycle at G0/G1 phases and promoted T cell apoptosis, which was associated with down-regulation of some related key genes transcription. These findings suggest that ADAR1 is essential for the maintenance of function of T lymphocytes during acute rejection. The mechanism underlying ADAR1’s action might include editing of a currently unknown substrate and interacting with other proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Aw MM, Verma A, Rela M et al (2008) Long-term outcome of mycophenolate mofetil rescue therapy for resistant acute allograft rejection in pediatric liver transplant recipients. Liver Transpl 14(9):1303–1308

    Article  PubMed  Google Scholar 

  2. Cardell M, Jung FJ, Zhai W et al (2008) Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion. J Pineal Res 44(3):261–266

    Article  CAS  PubMed  Google Scholar 

  3. Demirhan B, Bilezikci B, Haberal AN et al (2008) Hepatic parenchymal changes and histologic eosinophilia as predictors of subsequent acute liver allograft rejection. Liver Transpl 14(2):214–219

    Article  PubMed  Google Scholar 

  4. Nie Y, Ding L, Kao PN et al (2005) ADAR1 interacts with NF90 through double-stranded RNA and regulates NF90-mediated gene expression independently of RNA editing. Mol Cell Biol 25(16):6956–6963

    Article  CAS  PubMed  Google Scholar 

  5. Samuel CE (1998) Reoviruses and the interferon system. Curr Top Microbiol Immunol 233(Pt 2):125–145

    CAS  PubMed  Google Scholar 

  6. Wang Q, Miyakoda M, Yang W et al (2004) Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem 279(6):4952–4961

    Article  CAS  PubMed  Google Scholar 

  7. Nie Y, Hammond GL, Yang JH (2007) Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection. J Virol 81(2):917–923

    Article  CAS  PubMed  Google Scholar 

  8. Rabinovici R, Kabir K, Chen M et al (2001) ADAR1 is involved in the development of microvascular lung injury. Circ Res 88(10):1066–1071

    Article  CAS  PubMed  Google Scholar 

  9. Yang JH, Luo X, Nie Y et al (2003) Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation. Immunology 109(1):15–23

    Article  CAS  PubMed  Google Scholar 

  10. Yang JH, Nie Y, Zhao Q et al (2003) Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. J Biol Chem 278(46):45833–45842

    Article  CAS  PubMed  Google Scholar 

  11. Wang Q, Khillan J, Gadue P et al (2000) Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290(5497):1765–1768

    Article  CAS  PubMed  Google Scholar 

  12. Hartner JC, Schmittwolf C, Kispert A et al (2004) Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem 279(6):4894–4902

    Article  CAS  PubMed  Google Scholar 

  13. Wang H, Hou Z, Wu Y et al (2006) p150 ADAR1 isoform involved in maintenance of HeLa cell proliferation. BMC Cancer 6:282

    Article  PubMed  Google Scholar 

  14. Tomasoni S, Remuzzi G, Benigni A (2008) Allograft rejection: acute and chronic studies. Contrib Nephrol 159:122–134

    Article  CAS  PubMed  Google Scholar 

  15. Yuling H, Ruijing X, Xiang J et al (2008) Essential role of sphingosine-1-phosphate receptor 1-bearing CD8+ CD44+ CCR7+ T cells in acute skin allograft rejection. Am J Transplant 8(7):1401–1412

    Article  CAS  PubMed  Google Scholar 

  16. Falck P, Asberg A, Guldseth H et al (2008) Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients. Transplantation 85(2):179–184

    Article  CAS  PubMed  Google Scholar 

  17. Hall BM, Robinson CM, Plain KM et al (2008) Studies on naive CD4+ CD25+ T cells inhibition of naive CD4+ CD25- T cells in mixed lymphocyte cultures. Transpl Immunol 18(4):291–301

    Article  CAS  PubMed  Google Scholar 

  18. Zahn RC, Schelp I, Utermohlen O et al (2007) A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus. J Virol 81(2):457–464

    Article  CAS  PubMed  Google Scholar 

  19. Hartwig D, Schutte C, Warnecke J et al (2006) The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-alpha-stimulated host cells. J Viral Hepat 13(3):150–157

    Article  CAS  PubMed  Google Scholar 

  20. Patterson JB, Thomis DC, Hans SL et al (1995) Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. Virology 210(2):508–511

    Article  CAS  PubMed  Google Scholar 

  21. Longacre A, Storb U (2000) A novel cytidine deaminase affects antibody diversity. Cell 102(5):541–544

    Article  CAS  PubMed  Google Scholar 

  22. Muramatsu M, Kinoshita K, Fagarasan S et al (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102(5):553–563

    Article  CAS  PubMed  Google Scholar 

  23. Neuberger MS, Scott J (2000) Immunology. RNA editing AIDs antibody diversification? Science 289(5485):1705–1706

    Article  CAS  PubMed  Google Scholar 

  24. Eytan E, Braunstein I, Ganoth D et al (2008) Two different mitotic checkpoint inhibitors of the anaphase-promoting complex/cyclosome antagonize the action of the activator Cdc20. Proc Natl Acad Sci U S A 105(27):9181–9185

    Article  CAS  PubMed  Google Scholar 

  25. Kidokoro T, Tanikawa C, Furukawa Y et al (2008) CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene 27(11):1562–1571

    Article  CAS  PubMed  Google Scholar 

  26. Bassermann F, Frescas D, Guardavaccaro D et al (2008) The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 134(2):256–267

    Article  CAS  PubMed  Google Scholar 

  27. Berdougo E, Nachury MV, Jackson PK et al (2008) The nucleolar phosphatase Cdc14B is dispensable for chromosome segregation and mitotic exit in human cells. Cell Cycle 7(9):1184–1190

    CAS  PubMed  Google Scholar 

  28. Yamaguchi M, Fujimori-Tonou N, Yoshimura Y et al (2008) Mutation of DNA primase causes extensive apoptosis of retinal neurons through the activation of DNA damage checkpoint and tumor suppressor p53. Development 135(7):1247–1257

    Article  CAS  PubMed  Google Scholar 

  29. Huang H, Fletcher L, Beeharry N et al (2008) Abnormal cytokinesis after X-irradiation in tumor cells that override the G2 DNA damage checkpoint. Cancer Res 68(10):3724–3732

    Article  CAS  PubMed  Google Scholar 

  30. Liljeroos M, Vuolteenaho R, Rounioja S et al (2008) Bacterial ligand of TLR2 signals Stat activation via induction of IRF1/2 and interferon-alpha production. Cell Signal 20(10):1873–1881

    Article  CAS  PubMed  Google Scholar 

  31. Unutmaz D, Vilcek J (2008) IRF1: a deus ex machina in TH1 differentiation. Nat Immunol 9(1):9–10

    Article  CAS  PubMed  Google Scholar 

  32. Ahmad R, Raina D, Meyer C et al (2008) Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)—signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res 68(8):2920–2926

    Article  CAS  PubMed  Google Scholar 

  33. Xiang Z, Zhao Y, Mitaksov V et al (2008) Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. Blood 111(9):4809–4812

    Article  CAS  PubMed  Google Scholar 

  34. Jeong EG, Kim MS, Nam HK et al (2008) Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res 14(12):3716–3721

    Article  CAS  PubMed  Google Scholar 

  35. Shields BJ, Court NW, Hauser C et al (2008) Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signalling by the protein tyrosine phosphatase TCPTP. Cell Cycle 7(21):3405–3416

    CAS  PubMed  Google Scholar 

  36. Steiger SS, Fidler AE, Valcu M et al (2008) Avian olfactory receptor gene repertoires: evidence for a well-developed sense of smell in birds? Proc Biol Sci 275(1649):2309–2317

    Article  CAS  PubMed  Google Scholar 

  37. Cook BL, Ernberg KE, Chung H et al (2008) Study of a synthetic human olfactory receptor 17–4: expression and purification from an inducible mammalian cell line. PLoS ONE 3(8):e2920

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Natural Science Foundation of China Grants No. 30271281; No. 30170923; No. 30371399; No. 30571828.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Qingchuan Zhao or Kefeng Dou.

Additional information

Lei Cai and Yan Li contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, L., Li, Y., Liu, F. et al. The influence of ADAR1’s regulation on lymphocyte cell function during rejection. Mol Biol Rep 37, 2703–2709 (2010). https://doi.org/10.1007/s11033-009-9804-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-009-9804-z

Keywords

Navigation