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Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes

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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.

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Abbreviations

GR:

Glucocorticoid receptor

IL:

Interleukin

GRE:

Glucocorticoid response elements

Dex:

Dexamethasone

GSK:

Glycogen synthase kinase

VEGF:

Vascular endothelial growth factor

IFN-γ:

Interferon-γ

ACTH:

Adrenocorticotropic hormone

HGF:

Hepatocyte growth factor

TGF:

Transforming growth factor

IMQ:

Imiquimod

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Acknowledgments

The authors gratefully acknowledge the contributions of Yuelan Cao, Xianqi Zhang, Xinyan Huang, and Xianjie Wu to the development of this article. This research was supported by grants from the National Natural Science Foundation of China (81171496, 81171497, 30972643).

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Authors and Affiliations

  1. Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Xiao-Yong Man, Wei Li, Jia-Qi Chen, Jiong Zhou, Chun-Ming Li, Sui-Qing Cai & Min Zheng

  2. Department of Dermatology, University of Osnabrueck, Osnabrueck, Germany

    Lilla Landeck

  3. Department of Dermatology, Affiliated Hospital, Taishan Medical College, Taishan, China

    Kai-Hong Zhang & Zhen Mu

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  1. Xiao-Yong Man
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  2. Wei Li
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Correspondence to Min Zheng.

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X.-Y. Man, W. Li, J.-Q. Chen, and J. Zhou contributed equally to this work.

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Man, XY., Li, W., Chen, JQ. et al. Impaired nuclear translocation of glucocorticoid receptors: novel findings from psoriatic epidermal keratinocytes. Cell. Mol. Life Sci. 70, 2205–2220 (2013). https://doi.org/10.1007/s00018-012-1255-3

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