Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells.
Fibroblast growth factors (FGFs) are heparin-binding proteins crucial to embryogenesis, angiogenesis, and wound healing. FGF-1 is abundantly expressed in the synovium in rheumatoid arthritis and in rejecting allografts, sites of chronic immune-mediated inflammation. The frequency of FGF-1-responsive T cells is increased in the peripheral blood of these disorders, and a high percentage of infiltrating T cells in rheumatoid arthritis synovium express receptors for FGF-1. To understand the action of FGF-1 in T cells, studies were initiated in Jurkat T cells that express the signaling isoform of FGF receptor-1. These experiments show that FGF-1 stimulation of Jurkat T cells provides a second signal that augments TCR-mediated IL-2 production. Analogous to costimulation via CD28, this activity is mediated through activation of Rel/kappaB, a family of transcription factors known to regulate IL-2 and other activation-inducible proteins. FGF-1 alone induces modest nuclear translocation of kappaB-binding proteins, and this translocation is enhanced by the combination of anti-CD3 and FGF-1. This NF-kappaB binding complex is composed of transcriptionally active p65(RelA)/p50 heterodimers and results primarily from the targeted degradation of IkappaB-alpha, an inhibitor that sequesters Rel/kappaB in the cytoplasm. These data are the first to show a connection between FGF-1 signaling and NF-kappaB activation outside of embryonic development. The signaling events that link FGF receptor-1 engagement and NF-kappaB activation in Jurkat are probably distinct from the CD28 costimulation pathway, since FGF-1-induced Rel/kappaB binding proteins do not contain significant levels of c-Rel and are not identical with the CD28 response complex.
Byrd
V M
VM
Departments of Medicine and Microbiology/Immunology and Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. victor.m.byrd@vanderbilt.edu
Ballard
D W
DW
Miller
G G
GG
Thomas
J W
JW
D001692:Biological Transport; D018106:CD28 Antigens / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects*; D014158:Transcription, Genetic
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D000072000:NF-KappaB Inhibitor alpha; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1