Preclinical Evaluation of Local JAK1 and JAK2 Inhibition in Cutaneous Inflammation
| Autor: | Beth Thomas, Gregory Hollis, Patrick J. Haley, Brian Metcalf, Kris Vaddi, Claire L. Neilan, Jack G. Shi, Paul Collier, Nancy Contel, Steven Friedman, Swamy Yeleswaram, Jordan S. Fridman, Denise Hertel, Robert Collins, Stacey Shepard, Peggy Scherle, Timothy Burn, Robert C. Newton, James D. Rodgers |
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| Rok vydání: | 2011 |
| Předmět: |
Keratinocytes
STAT3 Transcription Factor Thymic stromal lymphopoietin Swine T-Lymphocytes medicine.medical_treatment Dermatology Biochemistry stat Dermatitis Atopic Pathogenesis Mice Psoriasis Nitriles Ustekinumab medicine Animals Humans Hypersensitivity Delayed Phosphorylation Protein Kinase Inhibitors Molecular Biology Cells Cultured business.industry Monocyte Janus Kinase 1 Cell Biology Atopic dermatitis Janus Kinase 2 medicine.disease Pyrimidines Cytokine medicine.anatomical_structure Epidermal Cells Immunology Pyrazoles Swine Miniature Chemokines business Signal Transduction medicine.drug |
| Zdroj: | Journal of Investigative Dermatology. 131:1838-1844 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2011.140 |
| Popis: | JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL-12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNγ) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values100 nM. In vivo, topical application of INCB018424 resulted in suppression of STAT3 phosphorylation, edema, lymphocyte infiltration, and keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing. |
| Databáze: | OpenAIRE |
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