A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.
A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.
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DOI：
10.4049/jimmunol.1501828
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发表时间：
2015-11-15
期刊：
影响因子：
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通讯作者：
Berg LJ
中科院分区：
文献类型：
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作者：
Cho HS;Shin HM;Haberstock-Debic H;Xing Y;Owens TD;Funk JO;Hill RJ;Bradshaw JM;Berg LJ
In T cells, the Tec kinases ITK and RLK are activated by TCR stimulation, and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/− Rlk−/− mice have indicated differential roles of ITK and RLK in TH1, TH2, and TH17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. Here, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro TH polarization experiments indicate that PRN694 is a potent inhibitor of TH1 and TH17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, TH1 and TH17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in TH1-mediated inflammatory diseases.
