RT Journal Article
SR Electronic
T1 Dose-dependent suppression of cytokine production from T cells by a novel phosphoinositide 3-kinase delta inhibitor (P6275)
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 193.7
OP 193.7
VO 190
IS 1 Supplement
A1 Way, Emily
A1 Chen, Kong
A1 Puri, Kamal
A1 Kolls, Jay
YR 2013
UL http://www.jimmunol.org/content/190/1_Supplement/193.7.abstract
AB The use of specific cytokine inhibitors to treat inflammatory conditions is common but typically utilizes monoclonal antibodies, fusion proteins, and other molecules whose large size necessitates parenteral administration. There remains a significant need for development of effective small molecule cytokine inhibitors for inflammatory conditions. Phosphoinositide 3-kinase (PI3K) plays a critical role in multiple cell signaling pathways, cell cycle progression, and cell growth, and is thus a potential target for drug development. We examined the effect of a novel PI3Kδ inhibitor on CD3/CD28 stimulated T-cell cytokine production. When added to culture after allowing naïve T-cells to polarize into effector T-cells, we observed dose-dependent suppression of multiple cytokines by Luminex and ELISA, including IL-17, IFNγ, and IL-4 from Th17, Th1, and Th2 cells, respectively. Real time PCR confirmed the suppression of cytokine gene expression suggesting the inhibition is mediated at the transcriptional level. However, we do not observe suppressed gene expression of Tbet, GATA3, or RORc, the critical transcription factors for production of those cytokines. A potential mechanism is that the PI3Kδ inhibitor alters nuclear localization of these transcription factors post-translationally. These experiments show effectiveness of this small molecule inhibitor of PI3Kδ activity to modulate inflammation in vitro and exhibit promise as a treatment for in vivo models of inflammation.