title: Cyr61/CCN1 is involved in the pathogenesis of psoriasis vulgaris via promoting IL-8 production by keratinocytes in a JNK/NF-κB pathway.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Pinru
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Xianjin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Gu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Rongfen
authors.initials: R
authors.lastname: Huo
authors.affiliation: Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Beiqing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Baihua
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Dermatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xdchen@medmail.com.cn.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Immunology, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ninglixiaoxue57@163.com.
authors.forename: Ningli
authors.initials: N
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D055815:Young Adult
chemical_list: D055515:Cysteine-Rich Protein 61; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha
keywords: Cyr61; IL-8; Keratinocyte; Neutrophils; Pathogenesis; Psoriasis vulgaris