CRAC channel inhibitors block cytokine production with a pattern distinguishable from cyclosporine (P5216)
| Autor: | Stephanie Ramos, Lori Butler, Trevor Kimbler, Jianguo Cao, Jonathan Grey, Evan Rogers, Zhijun Wang, Jeffrey Whitten, Jack Roos, Kenneth Stauderman, Gonul Velicelebi |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 190:212.5-212.5 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.190.supp.212.5 |
| Popis: | Engagement of the T cell receptor (TCR) triggers complex signaling cascades that result in various effector T cell responses. A critical component of TCR signaling is store-operated calcium entry (SOCE) that occurs through the activation of calcium release-activated calcium (CRAC) channels. Activated CRAC channels cause an increase in cytoplasmic calcium, which results in the transcription of calcineurin/NFAT-dependent genes involved in T cell proliferation and cytokine production. Both CRAC channel inhibitors and calcineurin inhibitors are known to inhibit T cell function. However, the relative impact of CRAC channel inhibitors and calcineurin inhibitors on Th1, Th2, Th17, and Treg functions are not known. Using anti-CD3/anti-CD28 to stimulate cytokine production by peripheral blood mononuclear cells (PBMCs), we demonstrate that novel CalciMedica CRAC channel inhibitors have a pattern of cytokine inhibition that is different from the calcineurin inhibitor cyclosporine (CsA). CRAC channel inhibitors inhibit Th1 and Th17 cytokines (IFNγ and IL-17) more potently than Treg and Th2 cytokines (IL-10 and IL-4), while CsA inhibits IL-10 more potently than IFNγ, IL-4, and IL-17. These results suggest that CRAC channel inhibitors and CsA have different potencies against different effector T cell subsets, and that CRAC channel inhibitors may achieve a more favorable balance of effects on pro- versus anti-inflammatory pathways in immune disorders. |
| Databáze: | OpenAIRE |
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