title: Effects of tacrolimus on IFN-γ signaling in keratinocytes: possible mechanisms by which tacrolimus affects IFN-γ-dependent skin inflammation.
abstract: Interferon-gamma (IFN-γ) signaling in keratinocytes plays an important role in IFN-γ-induced skin inflammation. A novel tacrolimus topical ointment has shown remarkable efficacy in treating skin inflammation. This study explored the mechanism of tacrolimus-modulated IFN-γ signal transduction in HaCaT keratinocytes and the effects of tacrolimus on IFN-γ-associated cytokine production in HaCaT cells. Tacrolimus down-regulated the recombinant human IFN-γ (rhIFN-γ)-induced expression of IFN-γ receptor α (IFN-γRα). The IFN-γ induced expression of phosphorylated Janus kinase 2 (pJAK2) and phosphorylated signal transducer and activator of transcription-1 (pSTAT-1) was also inhibited by tacrolimus. Tacrolimus up-regulated the IFN-γ-induced expression of suppressor of cytokine signaling-1 (SOCS-1). Tacrolimus was also demonstrated to down-regulate IFN-γ-induced the secretion of chemotactic factor CXCL-8 and the expression of intercellular adhesion molecule-1 and human leucocyte antigen HLA-DR. The findings in this work indicate that the direct effects of tacrolimus on IFN-γ signaling in keratinocytes may contribute to its therapeutic efficacy as a topical ointment in the treatment of IFN-γ-dependent skin inflammation.
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, China.
authors.forename: Hong-Qin
authors.initials: HQ
authors.lastname: Tu
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Li
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Tang
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Gao
authors.forename: Lan-Fang
authors.initials: LF
authors.lastname: Xu
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chen
authors.forename: Heng
authors.initials: H
authors.lastname: Gu
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000187:drug effects* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006684:HLA-DR Antigens; D007166:Immunosuppressive Agents; D016209:Interleukin-8; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D016559:Tacrolimus