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  • Title: Cyr61/CCN1 is involved in the pathogenesis of psoriasis vulgaris via promoting IL-8 production by keratinocytes in a JNK/NF-κB pathway.
    Author: Wu P, Ma G, Zhu X, Gu T, Zhang J, Sun Y, Xu H, Huo R, Wang B, Shen B, Chen X, Li N.
    Journal: Clin Immunol; 2017 Jan; 174():53-62. PubMed ID: 27856305.
    Abstract:
    PURPOSE: Interleukin-8 (IL-8) is an important factor in the pathogenesis of psoriasis vulgaris, which is characterized by proliferation of keratinocytes, neutrophil infiltration and angiogenesis. Cysteine-rich 61 (Cyr61/CCN1), a secreted extracellular matrix protein, is a novel proinflammatory factor. Whether Cyr61 is involved in the development of psoriasis vulgaris via IL-8 production remains unknown. In this study we explore the role of Cyr61 in IL-8 expression regulation in vivo and in vitro. METHODS: Skin samples from normal donors and psoriasis vulgaris patients were examined the profile of Cyr61 and IL-8 using immunohistochemistry, real-time PCR and Western blotting. HaCaT cells were treated with Cyr61 and IL-8 expression was analyzed by real-time PCR and ELISA. Signal transduction pathways in Cyr61-induced IL-8 production were investigated by real-time PCR, western blotting, luciferase reporter assay or chromatin immunoprecipitation (ChIP) assay. IMQ-induced psoriasis-like mice were treated with anti-Cyr61monoclonal antibodies (mAb), or IgG1 as a control. RESULTS: We found that Cyr61 was abundant in the epidermis of patients with psoriasis vulgaris and positively correlated with the pathogenesis of skin lesions. Cyr61 induced IL-8 production by keratinocytes in a dose dependent manner. This IL-8 synthesis occurred in an IL-1β- and TNF-α- independent mode via PI3K, AKT and JNK activation, with binding of enhanced AP-1, C/EBPβ and NF-κB to sites located in the IL-8 promoter region. Treatment with anti-Cyr61 mAb led to reduction of MIP-2 level, decreased neutrophil infiltration, and attenuated inflammation in vivo. CONCLUSIONS: Our results not only reveal a novel mechanism illustrating the role of Cyr61 in epidermis pathogenesis but also suggest that therapies targeting Cyr61 may represent a novel strategy in the treatment of psoriasis vulgaris.
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