title: Tacrolimus fails to regulate collagen expression in dermal fibroblasts.
abstract: BACKGROUND
  The purpose of this study was to investigate the effects of tacrolimus on human fibroblasts derived from unwounded skin, hypertrophic scars (HTS), and keloids. We hypothesized that tacrolimus, a potent anti-inflammatory and immunosuppressant drug known to attenuate solid organ transplant fibrosis, would block collagen expression in human dermal fibroblasts.
  
  
  METHODS
  We performed genomewide microarray analysis on human dermal fibroblasts treated with tacrolimus in vitro. We used principal component analysis and hierarchical clustering to identify targets regulated by tacrolimus. We performed quantitative polymerase chain reaction to validate the effect of tacrolimus on collagen 1 and 3 expression.
  
  
  RESULTS
  We identified 62, 136, and 185 gene probes on microarray analysis that were significantly regulated (P < 0.05) by tacrolimus in normal, HTS, and keloid fibroblasts, respectively. Collagen pathways were not blocked after tacrolimus exposure in any of the fibroblast groups; we validated these findings using quantitative polymerase chain reaction for collagen 1 and 3. Microarray gene expression of NME/NM23 nucleoside diphosphate kinase 1 and heterogeneous nuclear ribonucleoprotein H3-2H9 were significantly downregulated (P < 0.05) by tacrolimus in both HTS and keloid fibroblast populations but not normal fibroblasts.
  
  
  CONCLUSIONS
  Tacrolimus does not modulate the expression of collagen 1 or 3 in human dermal fibroblasts in vitro. Microarray gene expression of NME/NM23 nucleoside diphosphate kinase 1 and heterogeneous nuclear ribonucleoprotein H3-2H9 are blocked by tacrolimus in pathologic fibroblasts but not normal fibroblasts, and may represent novel genes underlying HTS and keloid pathogenesis. Tacrolimus-based anti-fibrotics might prove more effective if non-fibroblast populations such as inflammatory cells and keratinocytes are targeted.
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors: Victor W
authors: VW
authors: Wong
authors: Fanglei
authors: F
authors: You
authors: Michael
authors: M
authors: Januszyk
authors: Anna A
authors: AA
authors: Kuang
mesh_terms: D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D003094:Collagen / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D055106:Genome-Wide Association Study; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007627:Keloid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012867:Skin / Q000166:cytology / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D003094:Collagen; D016559:Tacrolimus
keywords: Fibroblast; Hypertrophic scar; Immunosuppression; Keloid; Wound healing