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Post‐transcriptional regulation of proinflammatory proteins
Author(s) -
Anderson Paul,
Phillips Kristine,
Stoecklin Georg,
Kedersha Nancy
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1103536
Subject(s) - tristetraprolin , proinflammatory cytokine , tumor necrosis factor alpha , arthritis , biology , messenger rna , lipopolysaccharide , inflammatory arthritis , untranslated region , rna binding protein , immunology , inflammation , gene , biochemistry
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.