LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation

Jin Gene Wang, Mark Collinge, Vinod Ramgolam, Oran Ayalon, Xinhao Cynthia Fan, Ruggero Pardi, Jeffrey R. Bender

Research output: Contribution to journalArticle

Abstract

Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the β2 integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-α, GM-CSF, and IL-3 mRNA, as well as a chimeric β-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA β-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-α ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-α or IFN-γ transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.

Original languageEnglish
Pages (from-to)2105-2113
Number of pages9
JournalJournal of Immunology
Volume176
Issue number4
Publication statusPublished - Feb 15 2006

Fingerprint

Lymphocyte Function-Associated Antigen-1
Cell Nucleus Active Transport
Cytokines
T-Lymphocytes
Messenger RNA
AU Rich Elements
Integrins
Granulocyte-Macrophage Colony-Stimulating Factor
Untranslated Regions
Enzyme-Linked Immunospot Assay
Globins
Lymphokines
Interleukin-3
RNA Stability
RNA Interference
Half-Life
Gene Expression
Peptides
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Wang, J. G., Collinge, M., Ramgolam, V., Ayalon, O., Fan, X. C., Pardi, R., & Bender, J. R. (2006). LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. Journal of Immunology, 176(4), 2105-2113.

LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. / Wang, Jin Gene; Collinge, Mark; Ramgolam, Vinod; Ayalon, Oran; Fan, Xinhao Cynthia; Pardi, Ruggero; Bender, Jeffrey R.

In: Journal of Immunology, Vol. 176, No. 4, 15.02.2006, p. 2105-2113.

Research output: Contribution to journalArticle

Wang, JG, Collinge, M, Ramgolam, V, Ayalon, O, Fan, XC, Pardi, R & Bender, JR 2006, 'LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation', Journal of Immunology, vol. 176, no. 4, pp. 2105-2113.
Wang JG, Collinge M, Ramgolam V, Ayalon O, Fan XC, Pardi R et al. LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. Journal of Immunology. 2006 Feb 15;176(4):2105-2113.
Wang, Jin Gene ; Collinge, Mark ; Ramgolam, Vinod ; Ayalon, Oran ; Fan, Xinhao Cynthia ; Pardi, Ruggero ; Bender, Jeffrey R. / LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. In: Journal of Immunology. 2006 ; Vol. 176, No. 4. pp. 2105-2113.
@article{2b4d7311e53a40ce8bbbf85f11b3fc35,
title = "LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation",
abstract = "Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the β2 integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-α, GM-CSF, and IL-3 mRNA, as well as a chimeric β-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA β-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-α ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-α or IFN-γ transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.",
author = "Wang, {Jin Gene} and Mark Collinge and Vinod Ramgolam and Oran Ayalon and Fan, {Xinhao Cynthia} and Ruggero Pardi and Bender, {Jeffrey R.}",
year = "2006",
month = "2",
day = "15",
language = "English",
volume = "176",
pages = "2105--2113",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "4",

}

TY - JOUR

T1 - LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation

AU - Wang, Jin Gene

AU - Collinge, Mark

AU - Ramgolam, Vinod

AU - Ayalon, Oran

AU - Fan, Xinhao Cynthia

AU - Pardi, Ruggero

AU - Bender, Jeffrey R.

PY - 2006/2/15

Y1 - 2006/2/15

N2 - Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the β2 integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-α, GM-CSF, and IL-3 mRNA, as well as a chimeric β-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA β-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-α ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-α or IFN-γ transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.

AB - Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the β2 integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-α, GM-CSF, and IL-3 mRNA, as well as a chimeric β-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA β-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-α ELISPOT assays. Furthermore, T cell stimulation by LFA-1 promotes rapid nuclear-to-cytoplasmic translocation of the mRNA-stabilizing protein HuR, which in turn is capable of binding an AU-rich element sequence in vitro. Abrogation of HuR function by use of inhibitory peptides, or marked reduction of HuR levels by RNA interference, prevents LFA-1 engagement-mediated stabilization of T cell TNF-α or IFN-γ transcripts, respectively. Thus, HuR-mediated mRNA stabilization, stimulated by integrin engagement and controlled at the level of HuR nuclear export, is critically involved in T cell activation.

UR - http://www.scopus.com/inward/record.url?scp=32044436324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=32044436324&partnerID=8YFLogxK

M3 - Article

C2 - 16455966

AN - SCOPUS:32044436324

VL - 176

SP - 2105

EP - 2113

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -