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In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies.

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

07/2015

Volume

195

Pages

265 - 276

Addresses

School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Keywords

Cell Line, Macrophages, Animals, Mice, Inbred C57BL, Mice, Salmonella typhimurium, Salmonella Infections, Animal, Inflammation, Lipopolysaccharides, Alanine, Serine, Phosphoproteins, Recombinant Fusion Proteins, RNA, Messenger, Cytokines, Amino Acid Substitution, Gene Expression, RNA Stability, Phosphorylation, Mutation, Female, Male, Tristetraprolin, Primary Cell Culture