Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.
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.
Phillips
Kristine
K
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
Kedersha
Nancy
N
Shen
Lily
L
Blackshear
Perry J
PJ
Anderson
Paul
P
D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006128:Growth; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases