title: Downregulation of TNIP1 Expression Leads to Increased Proliferation of Human Keratinocytes and Severer Psoriasis-Like Conditions in an Imiquimod-Induced Mouse Model of Dermatitis.
abstract: Psoriasis is a chronic, inflammatory skin disease involving both environmental and genetic factors. According to genome-wide association studies (GWAS), the TNIP1 gene, which encodes the TNF-α-induced protein 3-interacting protein 1 (TNIP1), is strongly linked to the susceptibility of psoriasis. TNIP1 is a widely expressed ubiquitin sensor that binds to the ubiquitin-editing protein A20 and restricts TNF- and TLR-induced signals. In our study, TNIP1 expression decreased in specimens of epidermis affected by psoriasis. Based on previous studies suggesting a role for TNIP1 in modulating cancer cell growth, we investigated its role in keratinocyte proliferation, which is clearly abnormal in psoriasis. To mimic the downregulation or upregulation of TNIP1 in HaCaT cells and primary human keratinocytes (PHKs), we used a TNIP1 specific small interfering hairpin RNA (TNIP1 shRNA) lentiviral vector or a recombinant TNIP1 (rTNIP1) lentiviral vector, respectively. Blocking TNIP1 expression increased keratinocyte proliferation, while overexpression of TNIP1 decreased keratinocyte proliferation. Furthermore, we showed that TNIP1 signaling might involve extracellular signal-regulated kinase1/2 (Erk1/2) and CCAAT/enhancer-binding protein β (C/EBPβ) activity. Intradermal injection of TNIP1 shRNA in BALB/c mice led to exaggerated psoriatic conditions in imiquimod (IMQ)-induced psoriasis-like dermatitis. These findings indicate that TNIP1 has a protective role in psoriasis and therefore could be a promising therapeutic target.
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Fangru
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Baiyu
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Liangjin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Qian
authors.affiliation: Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Hao
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000077271:Imiquimod; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011565:Psoriasis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D012720:Severity of Illness Index; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; C117046:TNIP1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077271:Imiquimod