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Inhibition of G-protein βγ signaling enhances T cell receptor-stimulated interleukin 2 transcription in CD4+ T helper cells.

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.
AuthorsEvan A Yost, Thomas R Hynes, Cassandra M Hartle, Braden J Ott, Catherine H Berlot
JournalPloS one (PLoS One) Vol. 10 Issue 1 Pg. e0116575 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID25629163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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
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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