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Title of the item:

Inhibition of G-Protein βγ Signaling Enhances T Cell Receptor-Stimulated Interleukin 2 Transcription in CD4+ T Helper Cells.

Title :
Inhibition of G-Protein βγ Signaling Enhances T Cell Receptor-Stimulated Interleukin 2 Transcription in CD4 T Helper Cells.
Authors :
Yost, Evan A.
Hynes, Thomas R.
Hartle, Cassandra M.
Ott, Braden J.
Berlot, Catherine H.
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Subject Terms :
G proteins
CELLULAR signal transduction
T cell receptors
INTERLEUKIN-2
CD4 antigen
T helper cells
GENETIC transcription
Source :
PLoS ONE; Jan2015, Vol. 10 Issue 1, p1-26, 26p
Academic Journal
G-protein-coupled receptor (GPCR) signaling modulates the expression of cytokines that are drug targets for immune disorders. However, although GPCRs are common targets for other diseases, there are few GPCR-based pharmaceuticals for inflammation. The purpose of this study was to determine whether targeting G-protein βγ (Gβγ) complexes could provide a useful new approach for modulating interleukin 2 (IL-2) levels in CD4+ T helper cells. Gallein, a small molecule inhibitor of Gβγ, increased levels of T cell receptor (TCR)-stimulated IL-2 mRNA in primary human naïve and memory CD4+ T helper cells and in Jurkat human CD4+ leukemia T cells. Gβ1 and Gβ2 mRNA accounted for >99% of Gβ mRNA, and small interfering RNA (siRNA)-mediated silencing of Gβ1 but not Gβ2 enhanced TCR-stimulated IL-2 mRNA increases. Blocking Gβγ enhanced TCR-stimulated increases in IL-2 transcription without affecting IL-2 mRNA stability. Blocking Gβγ also enhanced TCR-stimulated increases in nuclear localization of nuclear factor of activated T cells 1 (NFAT1), NFAT transcriptional activity, and levels of intracellular Ca2+. Potentiation of IL-2 transcription required continuous Gβγ inhibition during at least two days of TCR stimulation, suggesting that induction or repression of additional signaling proteins during T cell activation and differentiation might be involved. The potentiation of TCR-stimulated IL-2 transcription that results from blocking Gβγ in CD4+ T helper cells could have applications for autoimmune diseases. [ABSTRACT FROM AUTHOR]
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