Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Abstract

Interferon (IFN)-α is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lpr- and normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-α treatment. Analysis of IFN-α-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-α including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/lpr and/or BALB/c mice. Of IFN-α-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-α treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-α response in two lupus-prone models, and help to have an insight into the role of IFN-α in lupus pathogenesis

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL . Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 1979; 301: 5–8.

    Article  CAS  Google Scholar 

  2. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 2003; 100: 2610–2615.

    Article  CAS  Google Scholar 

  3. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003; 197: 711–723.

    Article  CAS  Google Scholar 

  4. Han GM, Chen SL, Shen N, Ye S, Bao CD, Gu YY . Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray. Genes Immun 2003; 4: 177–186.

    Article  CAS  Google Scholar 

  5. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK . Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005; 52: 1491–1503.

    Article  CAS  Google Scholar 

  6. Crow MK, Kirou KA, Wohlgemuth J . Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 2003; 36: 481–490.

    Article  CAS  Google Scholar 

  7. Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med 2003; 197: 777–788.

    Article  CAS  Google Scholar 

  8. Mathian A, Weinberg A, Gallegos M, Banchereau J, Koutouzov S . IFN-α induces early lethal lupus in preautoimmune (New Zealand Black × New Zealand White) F1 but not in BALB/c mice. J Immunol 2005; 174: 2499–2506.

    Article  CAS  Google Scholar 

  9. Hron JD, Peng SL . Type I IFN protects against murine lupus. J Immunol 2004; 173: 2134–2142.

    Article  CAS  Google Scholar 

  10. Schwarting A, Paul K, Tschirner S, Menke J, Hansen T, Brenner W et al. Interferon-β: a therapeutic for autoimmune lupus in MRL-Faslpr mice. J Am Soc Nephrol 2005; 16: 3264–3272.

    Article  CAS  Google Scholar 

  11. Hadj-Slimane R, Chelbi-Alix MK, Tovey MG, Bobe P . An essential role for IFN-α in the overexpression of Fas ligand on MRL/lpr lymphocytes and on their spontaneous Fas-mediated cytotoxic potential. J Interferon Cytokine Res 2004; 24: 717–728.

    Article  CAS  Google Scholar 

  12. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S . Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356: 314–317.

    Article  CAS  Google Scholar 

  13. Ronnblom LE, Alm GV, Oberg K . Autoimmune phenomena in patients with malignant carcinoid tumors during interferon-alpha treatment. Acta Oncol 1991; 30: 537–540.

    Article  CAS  Google Scholar 

  14. Niewold TB, Swedler WI . Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C. Clin Rheumatol 2005; 24: 178–181.

    Article  Google Scholar 

  15. Wandl UB, Nagel-Hiemke M, May D, Kreuzfelder E, Kloke O, Kranzhoff M et al. Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders. Clin Immunol Immunopathol 1992; 65: 70–74.

    Article  CAS  Google Scholar 

  16. Hahn BH . Animal models of systemic lupus erythematosus. In: Wallace DJ, Hahn BH (eds). Dubois’ Lupus Erythematosus, 6th edn. Lippincott Williams and Wilkins: Philadelphia, 2002, pp 339–388.

    Google Scholar 

  17. Theofilopoulos AN . Murine models of lupus. In: Lahita RG (eds). Systemic Lupus Erythematosus. Churchill Livingston: New York, 1992, pp 121.

    Google Scholar 

  18. Sharif MN, Tassiulas I, Hu Y, Mecklenbrauker I, Tarakhovsky A, Ivashkiv LB . IFN-α priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. J Immunol 2004; 172: 6476–6481.

    Article  CAS  Google Scholar 

  19. Dorner BG, Scheffold A, Rolph MS, Hüser MB, Kaufmann SHE, Radbruch A et al. MIP-1α, MIP-1β, RANTES, and ATAC/lymphotactin function together with IFN-γ as type 1 cytokines. Proc Natl Acad Sci USA 2002; 99: 6181–6186.

    Article  CAS  Google Scholar 

  20. Dyson N . The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–2262.

    Article  CAS  Google Scholar 

  21. Hamid T, Kakar SS . PTTG/securing activates expression of p53 and modulates its function. Mol Cancer 2004; 3: 18.

    Article  Google Scholar 

  22. Yu R, Heaney AP, Lu W, Chen J, Melmed S . Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p53-independent apoptosis. J Biol Chem 2000; 275: 36502–36505.

    Article  CAS  Google Scholar 

  23. Pusapati RV, Rounbehler RJ, Hong S, Powers JT, Yan M, Kiguchi K et al. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc. Proc Natl Acad Sci USA 2006; 103: 1446–1451.

    Article  CAS  Google Scholar 

  24. Fukushima T, Zapata JM, Singha NC, Thomas M, Kress CL, Krajewska M et al. Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity 2006; 24: 29–39.

    Article  CAS  Google Scholar 

  25. el-Deiry WS, Harper JW, O’Connor PM, Velcul escu VE, Canman CE, Jackman J et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994; 54: 1169–1174.

    CAS  PubMed  Google Scholar 

  26. Matsuoka M, Tani K, Asano S . Interferon-alpha-induced G1 phase arrest through up-regulated expression of CDK inhibitors, p19Ink4D and p21Cip1 in mouse macrophage. Oncogene 1998; 16: 2075–2086.

    Article  CAS  Google Scholar 

  27. Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC et al. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 1999; 18: 2892–2900.

    Article  CAS  Google Scholar 

  28. Santiago-Raber ML, Lawson BR, Dummer W, Barnhouseb M, Koundouris S, Wilson CB et al. Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol 2001; 167: 4067–4074.

    Article  CAS  Google Scholar 

  29. Goulvestre C, Chereau C, Nicco C, Mouthon L, Weill B, Batteux F . A mimic of p21WAF1/CIP1 ameliorates murine lupus. J Immunol 2005; 175: 6959–6967.

    Article  CAS  Google Scholar 

  30. Liu L, Tran E, Zhao YN, Huang YC, Flavell R, Lu BF . Gadd45β and Gadd45γ are critical for regulating autoimmunity. J Exp Med 2005; 202: 1341–1347.

    Article  CAS  Google Scholar 

  31. Waldmann TA . Targeting the interleukin-15/interleukin-15 receptor system in inflammatory autoimmune diseases. Arthritis Res Ther 2004; 6: 174–177.

    Article  CAS  Google Scholar 

  32. Moon JJ, Rubio ED, Martino A, Krumm A, Nelson BH . Permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of cyclin D2 by the interleukin-2 receptor. J Biol Chem 2004; 279: 5520–5527.

    Article  CAS  Google Scholar 

  33. Konttinen YT, Ainola M, Valleala H, Ma J, Ida H, Mandelin J et al. Analysis of 16 different matrix metalloproteinases (MMP-1–MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis 1999; 58: 691–697.

    Article  CAS  Google Scholar 

  34. Yahata T, de Caestecker MP, Lechleider RJ, Andriole S, Roberts AB, Isselbacher KJ et al. The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J Biol Chem 2000; 275: 8825–8834.

    Article  CAS  Google Scholar 

  35. Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, d’Eckner A et al. Cooperation of Stat2 and p300/CBP in signaling induced by interferon-a. Nature 1996; 383: 344–347.

    Article  CAS  Google Scholar 

  36. Sancho D, Gomez M, Viedma F, Esplugues E, Gordon-Alonso M, Garcia-Lopez MA et al. CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis. J Clin Invest 2003; 112: 872–882.

    Article  CAS  Google Scholar 

  37. Zhang H, Meng F, Chu CL, Takai T, Lowell CA . The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B. Immunity 2005; 22: 235–246.

    Article  Google Scholar 

  38. JØrgensen TN, Gubbels MR, Kotzin BL . Links between type I interferon and the genetic basis of disease in mouse lupus. Autoimmunity 2003; 36: 491–502.

    Article  Google Scholar 

  39. Vyse TJ, Drake CG, Rozzo SJ, Roper E, Izui S, Kotzin BL . Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice. J Clin Invest 1996; 98: 1762–1772.

    Article  CAS  Google Scholar 

  40. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK . Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994; 1: 219–229.

    Article  CAS  Google Scholar 

  41. Mohan C, Alas E, Morel L, Yang P, Wakeland EK . Genetic dissection of SLE pathogenesis Sle 1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 1998; 101: 1362–1372.

    Article  CAS  Google Scholar 

  42. Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D et al. Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 1994; 91: 10168–10172.

    Article  CAS  Google Scholar 

  43. Kawai T, Takeuchi O, Fujita T, Inoue JI, Mühlradt PF, Sato S et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 2001; 167: 5887–5894.

    Article  CAS  Google Scholar 

  44. Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1á/β-dependent gene expression in macrophages. Nat Immunol 2002; 3: 392–398.

    Article  CAS  Google Scholar 

  45. Wu C, Ohmori Y, Bandyopadhyay S, Sen G, Hamilton T . Interferon-stimulated response element and NFB sites cooperate to regulate double-stranded RNA-induced transc. J Interferon Res 1994; 6: 357–363.

    Article  Google Scholar 

  46. Nakaya T, Sato M, Hata N, Asagiri M, Suemori H, Noguchi S et al. Gene induction pathways mediated by distinct IRFs during viral infection. Biochem Biophys Res Commun 2001; 283: 1150–1156.

    Article  CAS  Google Scholar 

  47. Gresser I, Vignaux F, Belardelli F, Tovey MG, Maunoury MT . Injection of mice with antibody to mouse interferon α/β decreases the level of 2′–5′ oligoadenylate synthetase in peritoneal macrophages. J Virol 1985; 53: 221–227.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Qian L, Liu Y, Sun HB, Yokota H . Systems analysis of matrix metalloproteinase mRNA expression in skeletal tissues. Front Biosci 2002; 7: a126–a134.

    Article  Google Scholar 

  49. Li WQ, Dehnade F, Zafarullah M . Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J Immunol 2001; 166: 3491–3498.

    Article  CAS  Google Scholar 

  50. Sun HB, Zhu YX, Yin T, Sledge G, Yang YC . MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. Proc Natl Acad Sci USA 1998; 95: 13555–13560.

    Article  CAS  Google Scholar 

  51. Leung MK, Jones T, Michels CL, Livingston DM, Bhattacharya S . Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1. Genomics 1999; 61: 307–313.

    Article  CAS  Google Scholar 

  52. Tien ES, Davis JW, Vanden Heuvel JP . Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor a coregulator. J Biol Chem 2004; 279: 24053–24063.

    Article  CAS  Google Scholar 

  53. Delerive P, Fruchat JC, Staels B . Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 2001; 169: 453–459.

    Article  CAS  Google Scholar 

  54. Zhu M, John S, Berg M, Leonard WJ . Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell 1999; 96: 121–130.

    Article  CAS  Google Scholar 

  55. Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA et al. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med 2006; 3: 2274–2284.

    Article  CAS  Google Scholar 

  56. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I et al. Chemokine receptor specific for IP10 and Mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 1996; 184: 963–969.

    Article  CAS  Google Scholar 

  57. Elbourne KB, Keisler D, McMurray RW . Differential effects of estrogen and prolactin on autoimmune disease in the NZB/W mouse model of SLE. Lupus 1998; 7: 420–427.

    Article  CAS  Google Scholar 

  58. McMurray R, Keisler D, Kanuckel K, Izui S, Walker S . Prolactin influences autoimmune disease activity in the female NZB/W mouse. J Immunol 1991; 147: 3780–3787.

    CAS  PubMed  Google Scholar 

  59. Horwitz GA, Miklovsky I, Heaney AP, Ren SG, Melmed S . Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression. Mol Endocrinol 2003; 17: 600–609.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank HF Wang for assistance in data analysis. The work was supported by grants from the Shanghai Commission of Science and Technology (06JC14050), Shanghai leading Academic Discipline project (T0203), Chinese Natural Science Foundation Grant (30471613), China Postdoctoral Science Foundation (20060390634) and Shanghai Postdoctoral Science Foundation (06R214144).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N Shen.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, Q., Shen, N., Li, X. et al. Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice. Genes Immun 8, 590–603 (2007). https://doi.org/10.1038/sj.gene.6364421

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364421

Keywords

This article is cited by

Search

Quick links