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  • Title: Post-transcriptional regulation of proinflammatory proteins.
    Author: Anderson P, Phillips K, Stoecklin G, Kedersha N.
    Journal: J Leukoc Biol; 2004 Jul; 76(1):42-7. PubMed ID: 15075353.
    Abstract:
    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.
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