Keratin 17 as a therapeutic target for the treatment of psoriasis.
Keratin 17 (K17) is the only ectopically expressed keratin in psoriatic lesional epidermis. This review focuses mainly on reports that have addressed the mechanism of K17 up-regulation and its biological role in psoriasis. In addition to IFN-γ, IL-17A and IL-22, which are derived from Th17 and Th22 cells, could up-regulate K17 mRNA and protein levels in keratinocytes in a dose-dependent manner. Moreover, these effects are partially blocked with STAT1- and STAT3-specific inhibitors, as well as small interfering RNA (siRNA) targeting STAT1 and STAT3. On the other hand, the HLA DRB1*04 and/or *07 positive patients show significant T cell responses to two peptides from K17 protein selected on the basis of predicted HLA DRB1*04 and/or *07 bindings. One peptide contains the ALEEAN sequence, while the other peptide has an amino acid sequence that has not been previously reported. Analysis of these processes led us to propose the existence of a K17/T cells/cytokine autoimmune loop, in which ectopically expressed K17 impacts on the maintenance of psoriasis by activating autoreactive T cells. Furthermore, it has been found that altered peptide ligands, which are produced through single alanine residue substitutions at a critical TCR contact position, abolish the T cell proliferation and IFN-γ production induced by K17 pathogenic peptides. K17-specific antisense ODNs and RNAi suppress K17 mRNA and protein expression in psoriatic skin in vivo, which coincides with marked clinical and histological improvement. These findings highlight K17 as an attractive target for novel therapies aimed at curtailing psoriasis driven by chronic inflammation.
Department of Dermatology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, PR China.
Meng
M
Fu
Gang
G
Wang
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D053537:Keratin-17 / Q000502:physiology* / Q000627:therapeutic use*; D015603:Keratinocytes / Q000166:cytology; D008024:Ligands; D051379:Mice; D010455:Peptides / Q000737:chemistry; D011565:Psoriasis / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology; D015854:Up-Regulation; D000097043:Interleukin-22
D016207:Cytokines; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D053537:Keratin-17; D008024:Ligands; D010455:Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C494079:STAT1 protein, human; C494086:STAT3 protein, human