Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin

TLDR

Tumor necrosis factor‑α (TNF‑α) drives acute and chronic inflammation, and the CCCH zinc‑finger protein tristetraprolin (TTP) limits its production by binding the AU‑rich element of TNF‑α mRNA, destabilizing it, and is itself induced by TNF‑α‑stimulating agents. The study proposes that this TTP‑mediated negative feedback loop could be exploited as a target for anti‑TNF‑α therapies. The data demonstrate that TTP functions as a negative feedback regulator that destabilizes TNF‑α mRNA, thereby reducing TNF‑α production.

Abstract

Tumor necrosis factor–α (TNF-α) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-α production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-α messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-α production, including TNF-α itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-α production by destabilizing its messenger RNA. This pathway represents a potential target for anti–TNF-α therapies.