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Tyk2 is a therapeutic target for psoriasis-like skin inflammation.
- Source :
-
International immunology [Int Immunol] 2014 May; Vol. 26 (5), pp. 257-67. Date of Electronic Publication: 2013 Dec 17. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Blotting, Western
Calgranulin A genetics
Calgranulin A immunology
Cell Line
Cytokines immunology
Cytokines metabolism
Defensins genetics
Defensins immunology
Enzyme Inhibitors pharmacology
Gene Expression immunology
Humans
Hyperplasia immunology
Inflammation chemically induced
Inflammation prevention & control
Inflammation Mediators immunology
Inflammation Mediators metabolism
Interleukin-17 immunology
Interleukin-17 metabolism
Interleukin-23
Interleukins immunology
Interleukins metabolism
Interleukins pharmacology
Keratinocytes drug effects
Keratinocytes immunology
Keratinocytes metabolism
Mice, Inbred BALB C
Mice, Knockout
Psoriasis chemically induced
Psoriasis prevention & control
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction drug effects
Signal Transduction immunology
Skin metabolism
Skin pathology
TYK2 Kinase antagonists & inhibitors
TYK2 Kinase genetics
Tyrphostins pharmacology
Interleukin-22
Inflammation immunology
Psoriasis immunology
Skin immunology
TYK2 Kinase immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2377
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International immunology
- Publication Type :
- Academic Journal
- Accession number :
- 24345760
- Full Text :
- https://doi.org/10.1093/intimm/dxt062