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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0804063v1 183/3/2183    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chang, B. Y. Articles by Bullard, D. C. PubMed PubMed Citation Articles by Chang, B. Y. Articles by Bullard, D. C.

JAK3 Inhibition Significantly Attenuates Psoriasiform Skin Inflammation in CD18 Mutant PL/J Mice

Betty Y. Chang^1,*, Feifei Zhao^*, Xiaodong He, Hong Ren^*, Sylvia Braselmann^*, Vanessa Taylor^*, Joan Wicks, Donald G. Payan^*, Elliott B. Grossbard^*, Polly R. Pine^* and Daniel C. Bullard

^* Rigel Pharmaceuticals, Inc., South San Francisco, CA 94080; Department of Genetics, University of Alabama, Birmingham, AL 35294; and Histo-Scientific Research Laboratories, Mount Jackson, VA 22842

JAK3, a member of the Janus kinase family, is predominantly expressed in hemopoietic cells and binds specifically to the common 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Betty Y. Chang, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080. E-mail address: tamakoto{at}stanfordmedalumni.org

² Abbreviations used in this paper: Ct, threshold cycle number; qd, once daily orally.

³ The online version of this article contains supplemental material.