Tristetraprolin is a regulator of granulocyte-macrophage colony-stimulating factor mRNA stability

Abstract

Tristetraprolin (TTP) deficient mice exhibit a complex syndrome characterized by myeloid hyperplasia with extramedullary hematopoiesis, inflammation of skin and joints and cachexia. Macrophages derived from TTP-deficient mice accumulated twice as much TNFα mRNA and secreted 5-7 times more protein than control cells, and TNFα mRNA in these cells had an increased half-life (85 min in TTP-deficient cells versus 39 min in control cells). In transfection experiments, TTP can destabilize mRNAs containing the AU-rich elements from the 3′ untranslated region of both TNFα and GM-CSF mRNAs. To determine whether TTP was acting as a regulator of GM-CSF mRNA stability, we used primary cultures of bone marrow stromal cells (BMSC). In the absence of TTP, BMSC secreted 5-6 times more GM-CSF than control cells, and the steady-state levels of GM-CSF mRNA were also increased, due to the increased half-life of the message. Furthermore, we found that in the absence of TTP, the typical pattern of GM-CSF mRNA (two equally represented species of 0.8 and 1 kb) was changed, so that there was a clear predominance of the 1 kb species; this was found to be the fully polyadenylated form, whereas the 0.8 kb form appeared to be deadenylated. Thus, TTP-deficiency results in the increased accumulation of the fully polyadenylated form of GM-CSF mRNA. These date implicate TTP as a normal physiological regulator of GM-CSF mRNA stability and adenylation, and GM-CSF secretion. They also describe a novel biochemical target for the development of drugs to combat neutropenic conditions.