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Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2011-6. Epub 2004 Feb 9.

Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.

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Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.


TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor alpha (TNF-alpha). TIA-1 inhibits the translation of TNF-alpha transcripts, whereas TTP promotes the degradation of TNF-alpha transcripts. Here we show 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. Peritoneal macrophages derived from all three genotypes overexpress cyclooxygenase 2 and TNF-alpha. Surprisingly, lipopolysaccharide-activated TIA-1(-/-)TTP(-/-) macrophages secrete less TNF-alpha protein than either TIA-1(-/-) or TTP(-/-) macrophages. In these mice, arthritogenic cytokine may be produced by neutrophils that accumulate in the bone marrow and peripheral blood. Our results suggest that TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritogenic cytokines.

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