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.
Keywords:
IL-17; IL-22; IL-23; Tyk2; psoriasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Calgranulin A / genetics
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Calgranulin A / immunology
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Cell Line
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Cytokines / immunology
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Cytokines / metabolism
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Defensins / genetics
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Defensins / immunology
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Enzyme Inhibitors / pharmacology
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Gene Expression / immunology
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Humans
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Hyperplasia / immunology
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Inflammation / chemically induced
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Inflammation / immunology*
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Inflammation / prevention & control
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-22
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Interleukin-23
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Interleukins / immunology
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Interleukins / metabolism
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Interleukins / pharmacology
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Keratinocytes / drug effects
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Keratinocytes / immunology
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Keratinocytes / metabolism
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Mice, Inbred BALB C
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Mice, Knockout
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Psoriasis / chemically induced
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Psoriasis / immunology*
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Psoriasis / prevention & control
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Skin / immunology*
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Skin / metabolism
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Skin / pathology
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TYK2 Kinase / antagonists & inhibitors
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TYK2 Kinase / genetics
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TYK2 Kinase / immunology*
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Tyrphostins / pharmacology
Substances
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Calgranulin A
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Cytokines
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Defensins
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Enzyme Inhibitors
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Inflammation Mediators
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Interleukin-17
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Interleukin-23
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Interleukins
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Tyrphostins
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TYK2 Kinase
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tyrphostin A23