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 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.
authors.affiliation: Sections of Cardiovascular Medicine and Immunobiology, Vascular Biology and Transplant Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Jin Gene
authors.initials: JG
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Collinge
authors.forename: Vinod
authors.initials: V
authors.lastname: Ramgolam
authors.forename: Oran
authors.initials: O
authors.lastname: Ayalon
authors.forename: Xinhao Cynthia
authors.initials: XC
authors.lastname: Fan
authors.forename: Ruggero
authors.initials: R
authors.lastname: Pardi
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bender
mesh_terms: D021581:Active Transport, Cell Nucleus; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D018106:CD28 Antigens / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D018106:CD28 Antigens; D016207:Cytokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins