A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors
| Autor: | Hidenobu Kanda, Adam R. Johnson, Christopher A. Hurley, Mark Zak, Yingjie Lai, Kathy Barrett, Janusz J. Kulagowski, Wade S. Blair, Jan Smith, Christine Chang, Wenqian Yang, Sue J. Sohn, Hart S. Dengler, Nicholas Lewin-Koh, Lawren C. Wu, Birong Zhang, Aihe Zhou, Karen Williams, Nico Ghilardi, Jun Liang, Pawan Bir Kohli, Calum Macleod, Steven Magnuson, Anne van Abbema |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_treatment
Immunology Immunoblotting Locus (genetics) Biology Interleukin-23 Mice medicine Immunology and Allergy Animals Humans Protein Kinase Inhibitors TYK2 Kinase Janus kinase 1 Kinase Human patient Immunosuppression Interleukin-12 Cell biology Cytokine Tyrosine kinase 2 Cytokines Clinical and Human Immunology Tyrosine kinase Signal Transduction |
| Popis: | TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression. |
| Databáze: | OpenAIRE |
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