Post-transcriptional regulation of proinflammatory proteins

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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 α (TNF-α) than TIA-1−/− or TTP−/− macrophages. The bone marrows of these mice exhibit increased cellularity, reflecting the presence of mature neutrophils that secrete TNF-α in response to LPS stimulation. We hypothesize that TIA-1−/−TTP−/− neutrophils are a source of arthritigenic TNF-α, which promotes severe erosive arthritis in these mice.

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