title: Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22.
abstract: BACKGROUND
  Podoplanin (PDPN)/T1α/aggrus/PA2.26 antigen, a transmembranous glycoprotein, is a well-known lymphatic endothelial marker. Recent evidence indicates that PDPN is also expressed in keratinocytes especially of sebaceous glands.
  
  
  OBJECTIVE
  To verify expression-pattern and the regulatory mechanism of PDPN in human epidermal keratinocytes.
  
  
  METHODS
  PDPN-expression pattern was analyzed in normal and psoriatic epidermis by immunostaining. The regulatory mechanism of PDPN-expression of keratinocytes by cytokines was analyzed using specific inhibitors, siRNA, and adenoviral shRNA of signaling pathways.
  
  
  RESULTS
  In normal skin, PDPN was expressed on the basal cell layer of sebaceous glands and on the outer root sheath of hair follicles. While no expression was detected in the normal interfollicular epidermis, PDPN was detected in the basal cell layer of wound and hyperproliferative psoriatic epidermis, where the granular layer is lacking. TGF-β1 and IFN-γ independently upregulated PDPN-expression of keratinocytes via TGF-β receptor-Smad pathway and JAK-STAT pathway, respectively. IL-6 and IL-22 also stimulated PDPN-expression of keratinocytes accompanied by STAT-3 phosphorylation. siRNA of STAT-1, inhibitors of STAT-3 signaling, AG490, STAT-3 inhibitor VI, and si/shRNA of STAT-3 inhibited the PDPN-expression of keratinocytes induced by IFN-γ, IL-6 and IL-22 but not by TGF-β1.
  
  
  CONCLUSIONS
  These results indicate that TGF-β1, IFN-γ, IL-6, and IL-22 induce PDPN-expression of keratinocytes, which might be significantly involved in the wound healing process as well as in the pathomechanism of hyperproliferative psoriatic epidermis.
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Japan. wanwan@asahikawa-med.ac.jp
authors.forename: Masaru
authors.initials: M
authors.lastname: Honma
authors.forename: Masako
authors.initials: M
authors.lastname: Minami-Hori
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Iizuka
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing; D000097043:Interleukin-22; D000098853:Podoplanin
chemical_list: D007371:Interferon-gamma; D015850:Interleukin-6; D007378:Interleukins; D008562:Membrane Glycoproteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D000097043:Interleukin-22; C117468:PDPN protein, human; D000098853:Podoplanin; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human