Tacrolimus fails to regulate collagen expression in dermal fibroblasts

Victor W. Wong, Fanglei You, Michael Januszyk, Anna Kuang

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    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 inhuman 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.

    Original languageEnglish (US)
    Pages (from-to)678-690
    Number of pages13
    JournalJournal of Surgical Research
    Volume184
    Issue number1
    DOIs
    StatePublished - 2013

    Fingerprint

    Tacrolimus
    Collagen
    Fibroblasts
    Skin
    Hypertrophic Cicatrix
    Keloid
    NM23 Nucleoside Diphosphate Kinases
    Microarray Analysis
    Gene Expression
    Polymerase Chain Reaction
    Immunosuppressive Agents
    Principal Component Analysis
    Keratinocytes
    Population
    Genes
    Cluster Analysis
    Fibrosis
    Anti-Inflammatory Agents
    Down-Regulation
    Transplants

    Keywords

    • Fibroblast
    • Hypertrophic scar
    • Immunosuppression
    • Keloid
    • Wound healing

    ASJC Scopus subject areas

    • Surgery

    Cite this

    Tacrolimus fails to regulate collagen expression in dermal fibroblasts. / Wong, Victor W.; You, Fanglei; Januszyk, Michael; Kuang, Anna.

    In: Journal of Surgical Research, Vol. 184, No. 1, 2013, p. 678-690.

    Research output: Contribution to journalArticle

    Wong, Victor W. ; You, Fanglei ; Januszyk, Michael ; Kuang, Anna. / Tacrolimus fails to regulate collagen expression in dermal fibroblasts. In: Journal of Surgical Research. 2013 ; Vol. 184, No. 1. pp. 678-690.
    @article{24df014fb76d40c588e87d69a150bc77,
    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 inhuman 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.",
    keywords = "Fibroblast, Hypertrophic scar, Immunosuppression, Keloid, Wound healing",
    author = "Wong, {Victor W.} and Fanglei You and Michael Januszyk and Anna Kuang",
    year = "2013",
    doi = "10.1016/j.jss.2013.04.006",
    language = "English (US)",
    volume = "184",
    pages = "678--690",
    journal = "Journal of Surgical Research",
    issn = "0022-4804",
    publisher = "Academic Press Inc.",
    number = "1",

    }

    TY - JOUR

    T1 - Tacrolimus fails to regulate collagen expression in dermal fibroblasts

    AU - Wong, Victor W.

    AU - You, Fanglei

    AU - Januszyk, Michael

    AU - Kuang, Anna

    PY - 2013

    Y1 - 2013

    N2 - 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 inhuman 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.

    AB - 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 inhuman 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.

    KW - Fibroblast

    KW - Hypertrophic scar

    KW - Immunosuppression

    KW - Keloid

    KW - Wound healing

    UR - http://www.scopus.com/inward/record.url?scp=84884670367&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84884670367&partnerID=8YFLogxK

    U2 - 10.1016/j.jss.2013.04.006

    DO - 10.1016/j.jss.2013.04.006

    M3 - Article

    C2 - 23647800

    AN - SCOPUS:84884670367

    VL - 184

    SP - 678

    EP - 690

    JO - Journal of Surgical Research

    JF - Journal of Surgical Research

    SN - 0022-4804

    IS - 1

    ER -