Abstract |
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.
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Authors | Evan A Yost, Thomas R Hynes, Cassandra M Hartle, Braden J Ott, Catherine H Berlot |
Journal | PloS one
(PLoS One)
Vol. 10
Issue 1
Pg. e0116575
( 2015)
ISSN: 1932-6203 [Electronic] United States |
PMID | 25629163
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- G-protein Beta gamma
- GTP-Binding Protein beta Subunits
- GTP-Binding Protein gamma Subunits
- Interleukin-2
- NFATC Transcription Factors
- RNA, Messenger
- RNA, Small Interfering
- Receptors, Antigen, T-Cell
- Xanthenes
- gallein
- Calcium
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Topics |
- Calcium
(metabolism)
- Cell Line
- GTP-Binding Protein beta Subunits
(antagonists & inhibitors, metabolism)
- GTP-Binding Protein gamma Subunits
(antagonists & inhibitors, metabolism)
- Gene Expression Regulation
(drug effects)
- Gene Silencing
- Humans
- Interleukin-2
(genetics)
- NFATC Transcription Factors
(metabolism)
- Promoter Regions, Genetic
- Protein Transport
- RNA, Messenger
(genetics, metabolism)
- RNA, Small Interfering
(genetics)
- Receptors, Antigen, T-Cell
(metabolism)
- Signal Transduction
(drug effects)
- T-Lymphocytes, Helper-Inducer
(drug effects, metabolism)
- Time Factors
- Transcription, Genetic
- Xanthenes
(pharmacology)
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