Skip to main content

Advertisement

SpringerLink
Log in

Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. HUG95A Affymetrix DNA chips that contained oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student t-test statistic, revealed a complex regulation of molecular stress and immune gene responses. The majority of the 266 induced genes in affected and unaffected psoriatic skin were involved with interferon mediation, immunity, cell adhesion, cytoskeleton restructuring, protein trafficking and degradation, RNA regulation and degradation, signalling transduction, apoptosis and atypical epidermal cellular proliferation and differentiation. The disturbances in the normal protein degradation equilibrium of skin were reflected by the significant increase in the gene expression of various protease inhibitors and proteinases, including the induced components of the ATP/ubiquitin-dependent non-lysosomal proteolytic pathway that is involved with peptide processing and presentation to T cells. Some of the up-regulated genes, such as TGM1, IVL, FABP5, CSTA and SPRR, are well-known psoriatic markers involved in atypical epidermal cellular organization and differentiation. In the comparison between the affected and unaffected psoriatic skin, the transcription factor JUNB was found at the top of the statistical rankings for the up-regulated genes in affected skin, suggesting that it has an important but as yet undefined role in psoriasis. Our gene expression data and analysis suggest that psoriasis is a chronic interferon- and T-cell-mediated immune disease of the skin where the imbalance in epidermal cellular structure, growth and differentiation arises from the molecular antiviral stress signals initiating inappropriate immune responses.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Schon MP, Boehncke W-H (2005) Psoriasis. N Engl J Med 352:1899–1912

    Article  PubMed  Google Scholar 

  2. Weedon D (2002) Skin pathology, 2nd edn. Churchill Livingstone, London

    Google Scholar 

  3. Barker JNWN (1991) The pathophysiology of psoriasis. Lancet 338:227–230

    Article  PubMed  Google Scholar 

  4. McKenzie RC, Sabin E (2003) Aberrant signaling and transcription factor activation as an explanation for the defective growth control and differentiation of keratinocytes in psoriasis: a hypothesis (viewpoint). Exp Dermatol 12:337–345

    Article  PubMed  Google Scholar 

  5. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Lu Y-J, Gilliet M (2005) Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J Exp Med 202:135–143

    Article  PubMed  Google Scholar 

  6. Van der Fits L, van der Wel LI, Laman JD, Prens EP, Verschuren MCM (2003) In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-α sensitivity is unaltered. J Invest Dermatol 122:51–60

    Article  Google Scholar 

  7. Bowcock AM, Shannon W, Du F, Duncan J, Cao K, Aftergut K, Catier J, Fernandez-Vina M, Menter A (2001) Insights into psoriasis and other inflammatory diseases from large scale gene expression studies. Hum Mol Genet 10:1793–1805

    Article  PubMed  Google Scholar 

  8. Oestreicher JL, Walters IB, Kikuchi T, Gilleaudeau P, Surette J, Schwertschlag U, Dorner AJ, Krueger JG, Trepicchio WL (2001) Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling. Pharmacogenomics J 1:272–287

    PubMed  Google Scholar 

  9. Zhou X, Krueger JG, Kao M-CJ, Lee E, Du F, Menter A, Wong WH, Bowcock AM (2003) Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 13:69–78

    PubMed  Google Scholar 

  10. Nomura I, Gao B, Boguniewicz, Darst MA, Travers JB, Leung DYM (2003) Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J Allergy Clin Immunol 112:1195–1202

    Article  PubMed  Google Scholar 

  11. Van de Kerkhof PC, Gerritsen MJ, de Jong EM (1996) Transition from symptomless to lesional psoriatic skin. Clin Exp Dermatol 21:325–329

    Article  PubMed  Google Scholar 

  12. Yip SY (1984) The prevalence of psoriasis in the Mongoloid race. J Am Acad Dermatol 10:965–968

    PubMed  Google Scholar 

  13. Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680

    Article  PubMed  Google Scholar 

  14. Pontius JU, Wagner L, Schuler GD (2003) UniGene: a unified view of the transcriptome. In: The NCBI handbook. National Center for Biotechnology Information, Bethesda

    Google Scholar 

  15. Liu WM, Mei R, Di X, Ryder TB, Hubbell E, Dee S, Webster TA, Harrington CA, Ho MH, Baid J, Smeekens SP (2002) Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 18:1593–1599

    Article  PubMed  Google Scholar 

  16. Hubbell E, Liu WM, Mei R (2002) Robust estimators for expression analysis. Bioinformatics 18:1585–1592

    Article  PubMed  Google Scholar 

  17. Liu G, Loraine AE, Shigeta R, Cline M, Cheng J, Valmeekan V, Sun S, Kulp D, Siani-Rose MA (2003) NetAffx: affymetrix probesets and annotations. Nucleic Acids Res 31:82–86

    Article  PubMed  Google Scholar 

  18. Rodriguez LG, Guan JL (2005) 14-3-3 regulation of cell spreading and migration requires a functional amphipathic groove. J Cell Physiol 202:285–294

    Article  PubMed  Google Scholar 

  19. Higashi Y, Fuda H, Yanai H, Lee Y, Fukushige T, Kanzaki T, Strott CA (2004) Expression of cholesterol sulfotransferase (SULT2B1b) in human skin and primary cultures of human epidermal keratinocytes. J Invest Dermatol 122:1207–1213

    Article  PubMed  Google Scholar 

  20. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO (2004) Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumour necrosis factor-α. J Exp Med 199:731–736

    Article  PubMed  Google Scholar 

  21. Nickoloff BJ (2001) Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease (viewpoint). J Cutan Pathol 28:57–64

    Article  PubMed  Google Scholar 

  22. Kose K, Utas S, Yazici C, Akdas A, Kelestimur F (2001) Effect of propylthiouracil on adenosine deaminase activity and thyroid function in patients with psoriasis. Br J Dermatol 144:1121–1126

    Article  PubMed  Google Scholar 

  23. Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, Yancopoulos G, Cerretti DP, Daniel TO, Chen J (2002) Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res 1:2–11

    Article  PubMed  Google Scholar 

  24. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34:263–264

    Article  PubMed  Google Scholar 

  25. Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A (2003) HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nat Med 9:191–197

    Article  PubMed  Google Scholar 

  26. Chin KC, Cresswell P (2001) Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proc Natl Acad Sci U S A 98:15125–15130. Erratum in Proc Natl Acad Sci U S A 99:2460

    Article  PubMed  Google Scholar 

  27. Kumar M, Carmichael GC (1998) Antisense RNA: function and fate of duplex RNA in cells and higher eukaryotes. Microbiol Mol Biol Rev 62:1415–1434

    PubMed  Google Scholar 

  28. Behera AK, Kumar M, Lockey RF, Mohapatra SS (2002) 2′–5′ Oligoadenylate synthetase plays a critical role in interferon-gamma inhibition of respiratory syncytial virus infection of human epithelial cells. J Biol Chem 277:25601–25608

    Article  PubMed  Google Scholar 

  29. Jayan GC, Casey JL (2002) Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression. J Virol 76:12399–12404

    Article  PubMed  Google Scholar 

  30. Haque MA, Li P, Jackson SK, Zarour HM, Hawes JW, Phan UT, Maric M, Cresswell P, Blum JS (2002) Absence of gamma-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes. J Exp Med 195:1267–1277

    Article  PubMed  Google Scholar 

  31. Phan UT, Lackman RL, Cresswell P (2002) Role of the C-terminal propeptide in the activity and maturation of gamma-interferon-inducible lysosomal thiol reductase (GILT). Proc Natl Acad Sci U S A 99:12230–12298

    Article  PubMed  Google Scholar 

  32. Pernet I, Reymermier C, Guezennec A, Branka JE, Guesnet J, Perrier E, Dezutter-Dambuyant C, Schmitt D, Viac J (2003) Calcium triggers beta-defensin (hBD-2 and hBD-3) and chemokine macrophage inflammatory protein-3 alpha (MIP-3alpha/CCL20) expression in monolayers of activated human keratinocytes. Exp Dermatol 12:755–760

    Article  PubMed  Google Scholar 

  33. de Saint-Vis B, Vincent J, Vandenabeele S, Vanbervliet B, Pin JJ, Ait-Yahia S, Patel S, Mattei MG, Banchereau J, Zurawski S, Davoust J, Caux C, Lebecque S (1998) A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment. Immunity 9:325–336

    Article  PubMed  Google Scholar 

  34. Aractingi S, Briand N, Le Danff C, Viguier M, Bachelez H, Michel L, Dubertret L, Carosella ED (2001) HLA-G and NK receptor are expressed in psoriatic skin: a possible pathway for regulating infiltrating T cells? Am J Pathol 159:71–77

    PubMed  Google Scholar 

  35. Hilt W, Wolf DH (1996) Proteasomes: destruction as a programme. Trends Biochem Sci 21:96–102

    Article  PubMed  Google Scholar 

  36. Tanaka K, Kasahara M (1998) The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol Rev 163:161–176

    PubMed  Google Scholar 

  37. Yao T, Cohen RE (2002) A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419:403–407

    Article  PubMed  Google Scholar 

  38. Rock KL, Goldberg AL (1999) Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol 17:739–779

    Article  PubMed  Google Scholar 

  39. Iizuka H, Takahashi H, Honma M, Ishida-Yamamoto A (2004) Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death. J Dermatol 31:271–276

    PubMed  Google Scholar 

  40. Angel P, Karin M (1991) The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta 1072:129–157

    PubMed  Google Scholar 

  41. Beal MJ, Falciani F, Ghahramani Z, Rangel C, Wild DL (2005) A Bayesian approach to reconstructing genetic regulatory networks with hidden factors. Bioinformatics 21:349–356

    Article  PubMed  Google Scholar 

  42. Bakiri L (2000) Cell cycle-dependent variations in c-Jun and Junb phosphorylation: a role in the control of cyclin D1 expression. EMBO J 19:2056–2068

    Article  PubMed  Google Scholar 

  43. Johansen C, Kragballe K, Rasmussen M, Dam TN, Iversen L (2004) Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with non lesional psoriatic skin. Br J Dermatol 151:600–607

    Article  PubMed  Google Scholar 

  44. Szabowski A, Maas-Szabowski N, Andrecht S, Kolbus A, Schorpp-Kistner M, Fusenig NE, Angel P (2000) C-Jun and JunB antagonistically control cytokine-regulated mesenchymal–epidermal interaction in skin. Cell 103:745–755

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ormonde Waters for his assistance in the annotation of genes and the Japanese Society for Promotion of Science and the Australian Department of Industry Science and Resources for providing JKK, MB, and RT with travel grants to visit Japan.

Author information

Authors and Affiliations

  1. Centre for Bioinformatics and Biological Computing, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia

    Jerzy K. Kulski, William Kenworthy & Matthew Bellgard

  2. Department of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bouseidai, Isehara, Kanagawa, 259-1193, Japan

    Jerzy K. Kulski, Koichi Okamoto, Akira Oka, Gen Tamiya & Hidetoshi Inoko

  3. Department of Statistics, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia

    Ross Taplin

  4. Department of Dermatology, Tokai University School of Medicine, Bouseidai, Isehara, Kanagawa, 259-1193, Japan

    Tomotaka Mabuchi & Akira Ozawa

Authors
  1. Jerzy K. Kulski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William Kenworthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew Bellgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ross Taplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koichi Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akira Oka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomotaka Mabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akira Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gen Tamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hidetoshi Inoko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jerzy K. Kulski or Hidetoshi Inoko.

Additional information

The psoriasis gene expression data have been submitted to NCBI GEO under accession number GSE2737 with the release date of 1 October 2005

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kulski, J.K., Kenworthy, W., Bellgard, M. et al. Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals. J Mol Med 83, 964–975 (2005). https://doi.org/10.1007/s00109-005-0721-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0721-x

Keywords

Search

Navigation