Roles of tumor necrosis factor-alpha receptor subtypes in the pathogenesisof the tristetraprolin-deficiency syndrome

Tristetraprolin (TTP) is a member of the CCCH tandem zinc-finger class of p roteins. It can bind to and destabilize mRNAs encoding tumor necrosis facto r-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (G M-CSF). Conversely, mice deficient in TTP develop a complex syndrome charac terized by cachexia, myeloid hyperplasia, and joint and skin inflammation. Studies using anti-TNF-alpha neutralizing antibodies demonstrated that this syndrome, at least in part, is a consequence of the excess production of T NF-alpha in the absence of TTP. To evaluate the role played by each TNF-alp ha receptor in the pathogenesis of this syndrome, mice were generated that were deficient in TTP and either or both of the known TNF-alpha receptors ( TNFRs), type 1 (TNFR1) and type 2 (TNFR2). Mice deficient in TTP and TNFR1, or in TTP and both receptors, were protected from developing the TNF-alpha -induced cachexia and inflammation. In contrast, mice deficient in TNFR2 w ere more severely affected than mice deficient in TTP alone, suggesting tha t TNFR2 might play a protective role in the development of the syndrome. In cultured cells derived from these mice, apparent cooperation between the T NFRs was required to achieve normal TNF-alpha -induced expression of TTP, T NF-alpha, and GM-CSF mRNAs. Finally, the results showed that TNFR1 plays an important role in mediating TNF alpha -induced changes in TNF-alpha and GM CSF mRNA stability. (C) 2001 by The American Society of Hematology.