JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice.
JAK3, a member of the Janus kinase family, is predominantly expressed in hemopoietic cells and binds specifically to the common gamma chain of a subfamily of cytokine receptors that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Previous studies suggest that this tyrosine kinase plays key roles in mediating T cell functions, and inhibition of JAK3 has been shown to prevent graft rejection and decrease the severity of arthritis in rodent models. However, the functions of JAK3 in the development of skin immune responses and diseases such as psoriasis have not been determined. CD18 mutant PL/J mice develop spontaneous T cell-dependent psoriasiform skin disease with several similarities to human psoriasis. In this study, we treated mice with established skin disease with R348, a small molecule inhibitor of JAK3, and observed a marked attenuation of skin lesions following 6 wk of treatment. Histological analyses revealed major reductions of both epidermal and dermal lesion severity scores in R348-treated CD18-deficient PL/J mice compared with vehicle controls, which was associated with decreased CD4(+) T cell infiltration. In addition, systemic levels of IL-17, IL-22, IL-23, and TNF-alpha were significantly lower in mice receiving the compound, and T cells isolated from R348-treated mice also showed reduced phosphorylation of Stat5 after stimulation with IL-2. These findings suggest that small-molecule inhibitors of JAK3 may be useful in the treatment of inflammatory skin diseases such as psoriasis and strongly implicate JAK signaling events as important in the pathogenesis of this disease.
Chang
Betty Y
BY
Rigel Pharmaceuticals, Inc, South San Francisco, CA 94080, USA. tamakoto@stanfordmedalumni.org
Zhao
Feifei
F
He
Xiaodong
X
Ren
Hong
H
Braselmann
Sylvia
S
Taylor
Vanessa
V
Wicks
Joan
J
Payan
Donald G
DG
Grossbard
Elliott B
EB
Pine
Polly R
PR
Bullard
Daniel C
DC
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002633:Chemotaxis; D016207:Cytokines / Q000032:analysis; D007249:Inflammation / Q000188:drug therapy*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy* / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016896:Treatment Outcome
D018821:CD18 Antigens; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3