Ross, E.A. et al. (2015) Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin. Journal of Immunology, 195(1), pp. 265-276. (doi: 10.4049/jimmunol.1402826) (PMID:26002976) (PMCID:PMC4472942)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Morrice, Dr Nicholas |
| Authors: | Ross, E.A., Smallie, T., Ding, Q., O'Neil, J.D., Cunliffe, H.E., Tang, T., Rosner, D.R., Klevernic, I., Morrice, N.A., Monaco, C., Cunningham, A.F., Buckley, C.D., Saklatvala, J., Dean, J.L., and Clark, A.R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Journal of Immunology |
| Journal Abbr.: | J. Immunol. |
| Publisher: | American Association of Immunologists |
| ISSN: | 0022-1767 |
| ISSN (Online): | 1550-6606 |
| Copyright Holders: | Copyright © 2015 The Authors |
| First Published: | First published in Journal of Immunology 195(1):265-276 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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