Cyclosporin A induces the unfolded protein response in keratinocytes

Arch Dermatol Res. 2011 Sep;303(7):481-9. doi: 10.1007/s00403-010-1099-3. Epub 2011 Jan 11.


Psoriasis vulgaris is a chronic inflammatory disorder of the skin, in which activation of keratinocytes and crosstalk between keratinocytes and T cells or dendritic cells are considered to be involved in the pathogenesis of psoriasis vulgaris. Cyclosporin (Cy) A, an immunomodulator, has been used for the treatment of psoriasis vulgaris, but the mechanism of its action on keratinocytes has not been well elucidated as its function on T cells is well known. Previous study indicated that the expression of the unfolded protein response (UPR) markers, GRP78/Bip and HRD1 were poorly expressed in psoriasis vulgaris. To investigate if the UPR in keratinocytes is involved in the pathogenesis of psoriasis vulgaris we assessed immunocytochemistry of normal human skin and psoriatic lesions, quantitative PCR of keratinocyte cell line (HaCaT) treated with TGFβ. Moreover, to elucidate how CyA effects on the UPR in keratinocytes, we set out quantitative PCR and western blotting, HaCaT and squamous cell carcinoma cell lines (HSC-1) treated with CyA and CyA analog, cyclosporin D. Furthermore, the siRNA-mediated knockdown effect of cyclophilin (Cyp) A, Cyp B and Cyp C on HaCaT cells were also examined. As a result, the UPR was downregulated in keratinocytes from psoriatic lesions, characterized by immunocytochemical staining of GRP78/Bip, CHOP/GADD153, HRD1 and C/EBPβ. TGFβ induced UPR markers in HaCaT cells. CyA treatment and siRNA-mediated knockdown of Cyp B induced the UPR in HaCaT cells or HSC-1 cells. Altogether, we demonstrate that in psoriasis vulgaris CyA or reduction in Cyp B by RNA interference might induce the UPR in keratinocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cyclophilins / genetics
  • Cyclophilins / metabolism
  • Cyclosporine / pharmacology*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Psoriasis / genetics
  • Psoriasis / metabolism*
  • Psoriasis / pathology
  • RNA, Small Interfering / genetics
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transforming Growth Factor beta1 / immunology
  • Transforming Growth Factor beta1 / metabolism
  • Unfolded Protein Response* / genetics
  • Unfolded Protein Response* / immunology


  • DDIT3 protein, human
  • Heat-Shock Proteins
  • RNA, Small Interfering
  • Transforming Growth Factor beta1
  • cyclophilin B
  • Transcription Factor CHOP
  • Cyclosporine
  • Cyclophilins
  • molecular chaperone GRP78