Roles of tumor necrosis factor-α receptor subtypes in the pathogenesis of the tristetraprolin-deficiency syndrome

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Abstract
Tristetraprolin (TTP) is a member of the CCCH tandem zinc-finger class of proteins. It can bind to and destabilize mRNAs encoding tumor necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, mice deficient in TTP develop a complex syndrome characterized by cachexia, myeloid hyperplasia, and joint and skin inflammation. Studies using anti–TNF-α neutralizing antibodies demonstrated that this syndrome, at least in part, is a consequence of the excess production of TNF-α in the absence of TTP. To evaluate the role played by each TNF-α receptor in the pathogenesis of this syndrome, mice were generated that were deficient in TTP and either or both of the known TNF-α 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-α–induced cachexia and inflammation. In contrast, mice deficient in TNFR2 were more severely affected than mice deficient in TTP alone, suggesting that TNFR2 might play a protective role in the development of the syndrome. In cultured cells derived from these mice, apparent cooperation between the TNFRs was required to achieve normal TNF-α–induced expression of TTP, TNF-α, and GM-CSF mRNAs. Finally, the results showed that TNFR1 plays an important role in mediating TNF-α–induced changes in TNF-α and GM-CSF mRNA stability.

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