Pinru Wu1, Gang Ma2, Xianjin Zhu3, Ting Gu4, Jie Zhang5, Yue Sun5, Hui Xu6, Rongfen Huo5, Beiqing Wang6, Baihua Shen5, Xiangdong Chen7, Ningli Li8. 1. Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 3. Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Laboratory, Xie He Hospital, Fujian Medical University, Fujian, China. 4. Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 6. Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 7. Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xdchen@medmail.com.cn. 8. Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ninglixiaoxue57@163.com.
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.
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 vulgarispatients 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.