Published online before print April 1, 2004
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Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
1Correspondence: Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115. E-mail: panderson{at}rics.bwh.harvard.edu
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 
(TNF-) than TIA-1–/– or TTP–/– macrophages. The bone marrows of these mice exhibit increased cellularity, reflecting the presence of mature neutrophils that secrete TNF- in response to LPS stimulation. We hypothesize that TIA-1–/–TTP–/– neutrophils are a source of arthritigenic TNF-, which promotes severe erosive arthritis in these mice.
Key Words: tristetraprolin • T cell intracellular antigen-1 • adenine/uridine-rich elements
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