Post-transcriptional regulation of proinflammatory proteins.
Post-transcriptional mechanisms play a critical role in regulating the expression of numerous proteins that promote inflammatory arthritis. The mRNAs encoding a subset of these proteins possess adenine/uridine-rich elements (AREs) in their 3'-untranslated regions that profoundly influence the rate at which mRNA is degraded and translated into protein. Tristetraprolin (TTP) and T cell intracellular antigen-1 (TIA-1) are ARE-binding proteins that dampen the expression of this class of proteins by promoting mRNA degradation and protein translation, respectively. We have discovered that TIA-1 and TTP function as arthritis-suppressor genes: TIA-1-/- mice develop mild arthritis, TTP-/- mice develop severe arthritis, and TIA-1-/-TTP-/- mice develop very severe arthritis. Paradoxically, lipopolysaccharide (LPS)-activated macrophages derived from TIA-1-/-TTP-/- macrophages produce less tumor necrosis factor alpha (TNF-alpha) than TIA-1-/- or TTP-/- macrophages. The bone marrows of these mice exhibit increased cellularity, reflecting the presence of mature neutrophils that secrete TNF-alpha in response to LPS stimulation. We hypothesize that TIA-1-/-TTP-/- neutrophils are a source of arthritigenic TNF-alpha, which promotes severe erosive arthritis in these mice.
Anderson
Paul
P
Immunology and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA. panderson@rics.bwh.harvard.edu
Phillips
Kristine
K
Stoecklin
Georg
G
Kedersha
Nancy
N
D000818:Animals; D001168:Arthritis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D018448:Models, Immunological; D009504:Neutrophils / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; C076751:TIAL1 protein, human