JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation.
BACKGROUND
Using JAK inhibitors to inhibit cytokine signaling is presumed to be a possible means of treating skin inflammatory disorders such as contact dermatitis.


OBJECTIVE
To clarify the action site of JAK inhibitors in skin inflammatory disorders.


METHODS
We analyzed the mechanism of action of the JAK inhibitor JTE-052 using murine skin inflammation models, including contact hypersensitivity (CHS) and irritant contact dermatitis. Cells isolated from ear tissue or lymph node (LN) were analyzed by flow cytometry. The amounts of cytokines in the culture medium were measured by ELISA or bead array system. Proliferation of LN cells was evaluated by measurement of tritiated thymidine incorporation.


RESULTS
Oral administration of JTE-052 during both sensitization and elicitation phase attenuated CHS, but did not affect croton oil-induced irritant contact dermatitis. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro, and attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. JTE-052 did not affect hapten-induced cutaneous dendritic cell migration into draining lymph nodes or their costimulatory molecule expressions.


CONCLUSIONS
The JAK inhibitor JTE-052 exerts an inhibitory effect on antigen-specific T cell activation and subsequent inflammation in acquired skin immunity, such as CHS.
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Central Pharmaceutical Research Institute, Japan Tobacco, Japan.
Wataru
W
Amano
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Saeko
S
Nakajima
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Central Pharmaceutical Research Institute, Japan Tobacco, Japan.
Yasuo
Y
Yamamoto
Central Pharmaceutical Research Institute, Japan Tobacco, Japan.
Atsuo
A
Tanimoto
Central Pharmaceutical Research Institute, Japan Tobacco, Japan.
Mutsuyoshi
M
Matsushita
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshiki
Y
Miyachi
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
Kenji
K
Kabashima
D000284:Administration, Oral; D000818:Animals; D017951:Antigen Presentation; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003436:Croton Oil; D003713:Dendritic Cells / Q000166:cytology; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006241:Haptens / Q000276:immunology; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology*
D006241:Haptens; D018793:Interleukin-13; D020381:Interleukin-17; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D003436:Croton Oil; D007371:Interferon-gamma; C000621572:delgocitinib
Contact hypersensitivity; Cytokines; Effector memory T cell; JAK-STAT; Skin inflammation