title: CXCR3 ligands promote expression of functional indoleamine 2,3-dioxygenase in basal cell carcinoma keratinocytes.
abstract: BACKGROUND
  Basal cell carcinoma (BCC) is the most common malignancy in humans worldwide. Studies suggest that BCCs exhibit immunoprotection, similar to other keratinocyte carcinomas, although the mechanisms of defence have not been defined.
  
  
  OBJECTIVE
  To examine if indoleamine 2,3-dioxygenase (IDO), an immune privilege-associated enzyme, would be expressed in BCC, regulated in part by CXCR3.
  
  
  METHODS
  We analysed the expression and function of IDO in human BCC (hBCC) tissues using nonlesional skin epithelial (NL) tissues as a control.
  
  
  RESULTS
  Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) revealed significant upregulation of IDO1 and IDO2 (12·5- and 19·14-fold change, respectively) in nodular hBCCs as compared with NL tissues. Immunohistochemistry showed that IDO colocalized with keratin 17, a BCC keratinocyte marker, in hBCC tissues. Western blot identified a full-length IDO (42 kDa) product and a splice variant (∼30 kDa) in BCC tissues. Kynurenine assays and qPCR were conducted to determine IDO enzymatic activity in hBCCs in vitro with CXCL11 supplementation, which has previously been shown to be required for the tumour cell growth. Addition of CXCL11 upregulated IDO2 and increased l-kynurenine concentration in a dose-dependent manner in hBCCs while normal primary keratinocytes exhibited no response.
  
  
  CONCLUSIONS
  The expression of IDO at both mRNA and protein levels in hBCC tissues, the upregulation of IDO2 and the IDO-mediated l-kynurenine production in hBCCs with CXCL11 treatment suggest that functional IDO is synthesized by hBCC tumours and may be used as a method of immunoprotection during tumorigenesis. Also, IDO enzymatic activity may be modulated by CXCR3/CXCL11 signalling in BCCs.
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada.
authors.forename: B K K
authors.initials: BK
authors.lastname: Lo
authors.forename: R B
authors.initials: RB
authors.lastname: Jalili
authors.forename: D
authors.initials: D
authors.lastname: Zloty
authors.forename: A
authors.initials: A
authors.lastname: Ghahary
authors.forename: B
authors.initials: B
authors.lastname: Cowan
authors.forename: J P
authors.initials: JP
authors.lastname: Dutz
authors.forename: N
authors.initials: N
authors.lastname: Carr
authors.forename: J
authors.initials: J
authors.lastname: Shapiro
authors.forename: K J
authors.initials: KJ
authors.lastname: McElwee
mesh_terms: D002280:Basal Cell Carcinoma / Q000201:enzymology*; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology*; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D012313:RNA / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000502:physiology*; D012878:Skin Neoplasms / Q000201:enzymology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C515187:CXCR3 protein, human; D018076:DNA, Complementary; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D054367:Receptors, CXCR3; D007737:Kynurenine; D012313:RNA