title: Tyk2 is a therapeutic target for psoriasis-like skin inflammation.
abstract: Tyrosine kinase 2 (Tyk2), a member of the Jak kinase family, mediates signals triggered by various cytokines, which are related to the pathogenesis of psoriasis. In this study, we investigated the role of Tyk2 in IL-23-induced psoriasis-like skin inflammation. Tyk2(-/-) mice when injected with IL-23 showed significantly reduced ear skin swelling with epidermal hyperplasia and inflammatory cell infiltration compared with wild-type mice. In addition, Tyk2 deficiency reduced production of pro-inflammatory cytokines and psoriasis-relevant anti-microbial peptides. More noteworthy is that Tyk2 directly regulated IL-22-dependent inflammation and epidermal hyperplasia. Taken together with the inhibition of IL-23-induced inflammation by treatment with neutralizing antibodies against IL-17 or IL-22, Tyk2 participates in both IL-23 and IL-22 signal transduction to mediate psoriasis-like skin inflammation. On the basis of these findings, we demonstrated for the first time that a small-molecule Tyk2 inhibitor significantly inhibited IL-23-induced inflammation and cytokine production in the skin. These observations demonstrate the important role of Tyk2 in experimental skin inflammation and indicate the therapeutic potential of Tyk2 inhibition in human psoriasis.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishizaki
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Akimoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Manish
authors.initials: M
authors.lastname: Diwan
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maeda
authors.forename: Sumihito
authors.initials: S
authors.lastname: Togi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Kenji
authors.initials: K
authors.lastname: Oritani
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D023082:Defensins / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D006965:Hyperplasia / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23; D007378:Interleukins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020032:Tyrphostins / Q000494:pharmacology; D000097043:Interleukin-22
chemical_list: D040501:Calgranulin A; D016207:Cytokines; D023082:Defensins; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D053634:TYK2 Kinase; D020032:Tyrphostins; D000097043:Interleukin-22; C060641:tyrphostin A23
keywords: IL-17; IL-22; IL-23; Tyk2; psoriasis