| First Author | Qiu LQ | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 10 | Pages | 5150-9 |
| PubMed ID | 22491258 | Mgi Jnum | J:188677 |
| Mgi Id | MGI:5441422 | Doi | 10.4049/jimmunol.1103700 |
| Citation | Qiu LQ, et al. (2012) Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. J Immunol 188(10):5150-9 |
| abstractText | Tristetraprolin (TTP) is a mRNA-destabilizing protein that binds to AU-rich elements in labile transcripts, such as the mRNA encoding TNF, and promotes their deadenylation and degradation. TTP-deficient (knockout [KO]) mice exhibit an early-onset, severe inflammatory phenotype, with cachexia, erosive arthritis, left-sided cardiac valvulitis, myeloid hyperplasia, and autoimmunity, which can be prevented by injections of anti-TNF Abs, or interbreeding with TNF receptor-deficient mice. To determine whether the excess TNF that causes the TTP KO phenotype is produced by myeloid cells, we performed myeloid-specific disruption of Zfp36, the gene encoding TTP. We documented the lack of TTP expression in LPS-stimulated bone marrow-derived macrophages from the mice, whereas fibroblasts expressed TTP mRNA and protein normally in response to serum. The mice exhibited a minimal phenotype, characterized by slight slowing of weight gain late in the first year of life, compared with the early-onset, severe weight loss and inflammation seen in the TTP KO mice. Instead, the myeloid-specific TTP KO mice were highly and abnormally susceptible to a low-dose LPS challenge, with rapid development of typical endotoxemia signs and extensive organ damage, and elevations of serum TNF levels to 110-fold greater than control. We conclude that myeloid-specific TTP deficiency does not phenocopy complete TTP deficiency in C57BL/6 mice under normal laboratory conditions, implying contributions from other cell types to the complete phenotype. However, myeloid cell TTP plays a critical role in protecting mice against LPS-induced septic shock, primarily through its posttranscriptional regulation of TNF mRNA stability. |
