Archives of Dermatological Research

, Volume 300, Issue 1, pp 37–45

The role of heparin-binding EGF-like growth factor and amphiregulin in the epidermal proliferation of psoriasis in cooperation with TNFα

  • Aki Yoshida
  • Hiroyuki Kanno
  • Daisuke Watabe
  • Toshihide Akasaka
  • Takashi Sawai
Original Paper

DOI: 10.1007/s00403-007-0809-y

Cite this article as:
Yoshida, A., Kanno, H., Watabe, D. et al. Arch Dermatol Res (2008) 300: 37. doi:10.1007/s00403-007-0809-y


Heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AREG) are the members of EGF family that bind to common EGF receptor (EGFR) in the epidermis. However, the role of these two growth factors in epidermal hyperplasia of psoriasis has not been established. On the other hand, CD4+ T cells are responsible for the development of the psoriatic plaques. However, inflammatory cytokines, such as TNFα, IL-1β and IFNγ, inhibit the growth of human keratinocytes in vitro. The expression of HB-EGF, AREG and EGFR proteins in normal (n = 22) and psoriatic (n = 34) skin tissues was examined by immunohistochemistry. Then, the effects of HB-EGF and AREG on the growth of cultured adult normal human epidermal keratinocytes (NHEK-AD) with or without TH1 cytokines, such as TNFα, IL-1β and IFNγ, were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and the effects of these cytokines on the expression of EGFR mRNA in NHEK-AD were examined by real-time reverse transcriptase-polymerase chain reaction. The expression of HB-EGF and AREG in the epidermis was not specific to psoriatic plaques, but the distribution of positive cells throughout the epidermis was different between normal skins and psoriatic plaques. On the other hand, in the dermis and the papillary dermis, most of vascular endothelial cells and infiltrating mononuclear cells expressed both HB-EGF and AREG in normal skins and psoriatic plaques, and these positive cells were more frequent in psoriasis compared to normal skin. In the in vitro growth assay, HB-EGF, not AREG, stimulated the proliferation of NHEK-AD at the optimal concentration of 1 ng/ml. Furthermore, HB-EGF compensated the growth-suppressing effects of TNFα, IL-1β and IFNγ on NHEK-AD, and TNFα promoted the growth of NHEK-AD at the concentration of 2 and 20 U/ml in combination with HB-EGF and, in lesser extent, with AREG. However, TNFα did not affect the expression of EGFR mRNA in NHEK-AD. Growth factors and inflammatory cytokines produced in the dermis would be important for the epidermal proliferation in psoriatic plaques and TNFα may play a key role in cooperation with HB-EGF and AREG in the proliferation of epidermal keratinocytes at the psoriatic skin lesions.


Amphiregulin Heparin-binding EGF-like growth factor Keratinocyte Psoriasis TNFα 





Bovine pituitary extract


Epidermal growth factor


Epidermal growth factor receptor


Glyceraldehyde-3-phosphate dehydrogenase


Heparin-binding epidermal growth factor-like growth factor






3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide


Adult normal human epidermal keratinocytes


Psoriasis area and severity index


Reverse transcriptase-polymerase chain reaction


Transforming growth factor


Tumor necrosis factor

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Aki Yoshida
    • 1
  • Hiroyuki Kanno
    • 1
  • Daisuke Watabe
    • 2
  • Toshihide Akasaka
    • 2
  • Takashi Sawai
    • 1
  1. 1.Department of PathologyIwate Medical University School of MedicineMoriokaJapan
  2. 2.Department of DermatologyIwate Medical University School of MedicineMoriokaJapan

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