Mutational analysis of TNF-alpha gene reveals a regulatory role for the 3'-untranslated region in the genetic predisposition to lupus-like autoimmune disease.

Abstract

Lupus-prone mice show reduced production of TNF-alpha and, upon long-term treatment with recombinant TNF-alpha, significant protection from disease development. Mutational analysis of the 5'-untranslated region (UTR) and 3'-UTR of the mouse TNF-alpha gene reveals a marked degree of polymorphism. Transient expression experiments in the RAW 264.7 macrophage-like cell line using the luciferase reporter system suggest an important role for the mutations in the 3'-UTR in the biosynthesis of TNF-alpha, and provide a molecular explanation for the reduced TNF-alpha production in lupus-prone NZW mice.