New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of β-defensins, LL37, and TLR2

Koji Sayama, Hitoshi Komatsuzawa, Kenshi Yamasaki, Yuji Shirakata, Yasushi Hanakawa, Kazuhisa Ouhara, Sho Tokumaru, Xiuju Dai, Mikiko Tohyama, Peter ten Dijke, Motoyuki Sugai, Hidenori Ichijo, Koji Hashimoto

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital. This characteristic feature is formed during differentiation. Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses β-defensins 1-3 and LL37. We hypothesized that epidermal keratinocytes develop an innate immune barrier based on human β-defensins (hBD) and LL37 during differentiation. To prove this, we introduced an active form of the apoptosis signal-regulating kinase-1 (ASK1), an intracellular regulator of keratinocyte differentiation, into cultured normal human keratinocytes. Transfection of this active form, ASK1-ΔN, significantly enhanced the expression of hBD1-3 and LL37. In addition, a p38 inhibitor abolished this induction, indicating that the ASK1-p38 cascade regulates the expression of hBD1-3 and LL37. Furthermore, the ASK1-p38 pathway also regulated the expression of Toll-like receptor (TLR)2 in keratinocytes. Contact between S. aureus and keratinocytes resulted in the phosphorylation of p38 and induced the expression of hBD2 and hBD3. Moreover, the p38 inhibitor reduced this induction. In conclusion, the ASK1-p38 cascade regulates the innate immunity of the skin by forming an immune barrier consisting of hBD, LL37, and TLR2 during epidermal differentiation.

Original languageEnglish
Pages (from-to)1886-1895
Number of pages10
JournalEuropean Journal of Immunology
Volume35
Issue number6
DOIs
Publication statusPublished - 2005 Jun 1
Externally publishedYes

Keywords

  • ASK1
  • Keratinocyte
  • LL37
  • TLR2
  • β-defensins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of β-defensins, LL37, and TLR2'. Together they form a unique fingerprint.

  • Cite this

    Sayama, K., Komatsuzawa, H., Yamasaki, K., Shirakata, Y., Hanakawa, Y., Ouhara, K., Tokumaru, S., Dai, X., Tohyama, M., ten Dijke, P., Sugai, M., Ichijo, H., & Hashimoto, K. (2005). New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of β-defensins, LL37, and TLR2. European Journal of Immunology, 35(6), 1886-1895. https://doi.org/10.1002/eji.200425827