title: Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes.
abstract: Psoriasis is a chronic proliferative skin disease and is usually treated with topical glucocorticoids, which act through the glucocorticoid receptor (GR), a component of the physiological systems essential for immune responses, differentiation, and homeostasis. To investigate the possible role of GR in the pathogenesis of psoriasis, normal and psoriatic lesional skin were recruited. Firstly, the immunolocalization of GR in the skin and cultured epidermal keratinocytes were determined by immunofluorescence. In normal skin and cultured human epidermal keratinocytes, intracellular GR is localized in the nuclei, while in psoriatic skin and cultured keratinocytes, GR is in the cytoplasm. Next, we investigated possible factors associated with the cytoplasmic distribution. We found that VEGF and IFN-γ led to impaired nuclear translocation of GR through p53 and microtubule-inhibitor, vincristine, and inhibited nuclear uptake of GR in normal keratinocytes. In addition to dexamethasone, interleukin (IL)-13 was also able to transfer GR into nuclei of psoriatic keratinocytes. Furthermore, discontinuation of dexamethasone induced cytoplasmic retention of GR in normal keratinocytes. In contrast, energy depletion of normal epidermal keratinocytes did not change the nuclear distribution of GR. To confirm our findings in vivo, an imiquimod-induced psoriasis-like skin mouse model was included. IL-13 ameliorated (but vincristine exacerbated) the skin lesions on the mouse. Taken together, our findings define that impaired nuclear translocation of GR is associated with VEGF, IFN-γ, p53, and microtubule. Therapeutic strategies designed to accumulate GR in the nucleus, such as IL-13, may be beneficial for the therapy of psoriasis.
authors: Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
authors: Xiao-Yong
authors: XY
authors: Man
authors: Wei
authors: W
authors: Li
authors: Jia-Qi
authors: JQ
authors: Chen
authors: Jiong
authors: J
authors: Zhou
authors: Lilla
authors: L
authors: Landeck
authors: Kai-Hong
authors: KH
authors: Zhang
authors: Zhen
authors: Z
authors: Mu
authors: Chun-Ming
authors: CM
authors: Li
authors: Sui-Qing
authors: SQ
authors: Cai
authors: Min
authors: M
authors: Zheng
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D000078404:Epidermal Cells; D005455:Fluorescent Antibody Technique; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D011565:Psoriasis / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018793:Interleukin-13; D011965:Receptors, Glucocorticoid; D042461:Vascular Endothelial Growth Factor A; D014750:Vincristine; D003907:Dexamethasone; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone