Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability

Deficiency of tristetraprolin (TTP), the prototype of the CCCH zinc finger proteins, results in a complex inflammatory syndrome in mice. Most aspects of the syndrome are secondary to excess circulating tumor necrosis factor ( TNF)-alpha, a consequence of increased stability of TNF-alpha messenger RNA (mRNA) in TTP-deficient macrophages. TTP can bind directly to the AU-rich element in TNF-alpha mRNA, increasing its lability, Here we show that TTP d eficiency also results in increased cellular production of granulocyte-macr ophage colony-stimulating factor (GM-CSF) and increased stability of its mR NA, apparently secondary to decreased deadenylation. Similar findings were observed in mice also lacking both types of TNF-alpha receptors, excluding excess TNF-alpha production as a cause of the increased GM-CSF mRNA levels and stability. TTP appears to be a physiological regulator of GM-CSF mRNA d eadenylation and stability. (C) 2000 by The American Society of Hematology.