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

J Immunol. 2006 Feb 15;176(4):2105-13. doi: 10.4049/jimmunol.176.4.2105.

Abstract

Lymphokine gene expression is a precisely regulated process in T cell-mediated immune responses. In this study we demonstrate that engagement of the beta(2) integrin LFA-1 in human peripheral T cells markedly extends the half-life of TNF-alpha, GM-CSF, and IL-3 mRNA, as well as a chimeric beta-globin mRNA reporter construct containing a strongly destabilizing class II AU-rich element from the GM-CSF mRNA 3'-untranslated region. This integrin-enhanced mRNA stability leads to augmented protein production, as determined by TNF-alpha 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-alpha or IFN-gamma 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism*
  • Base Sequence
  • CD28 Antigens / pharmacology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cytokines / genetics*
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Humans
  • Lymphocyte Activation* / drug effects
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Lymphocyte Function-Associated Antigen-1 / pharmacology*
  • Molecular Sequence Data
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, Surface
  • CD28 Antigens
  • Cytokines
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Lymphocyte Function-Associated Antigen-1
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins