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Zinc finger protein tristetraprolin (TTP) modulates macrophage inflammatory activity by destabilizing cytokine mRNAs. In this study, through a screen of TTP-bound mRNAs in activated human macrophages, we have identified CCL3 mRNA as the most abundantly bound TTP target mRNA and have characterized this interaction via conserved AU-rich elements. Compared to the wild-type cells, TTP(-/-) macrophages produced higher levels of LPS-induced CCL3. In addition, the plasma level of CCL3 in TTP(-/-) mice was markedly higher than that in wild-type mice. To determine the in vivo significance of TTP-regulated CCL3, we generated CCL3(-/-)TTP(-/-) double-knockout mice. Along with decreased proinflammatory cytokines in their paw joints, there were significant functional and histologic improvements in the inflammatory arthritis of TTP(-/-) mice when CCL3 was absent, although cachexia, reflecting systemic inflammation, was notably unaffected. Furthermore, the marked exacerbation of aortic plaque formation caused by TTP deficiency in the APOE(-/-) mouse model of atherosclerosis was also rescued by disrupting CCL3. Taken together, our data indicate that the interaction between TTP and CCL3 mRNA plays an important role in modulating localized inflammatory processes in tissues that are dissociated from the systemic manifestations of chronic inflammation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159726 | PMC |
| http://dx.doi.org/10.4049/jimmunol.1101149 | DOI Listing |
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Article Synopsis
- Basophils are rare immune cells that play vital roles in allergic reactions and defense against parasites, but how they activate and produce inflammation is not well understood, prompting research into RNA-binding proteins like tristetraprolin (TTP).
- Through various experiments, including RNA sequencing and mRNA stability assays on TTP-deficient mice, the study found that without TTP, basophils produce more inflammatory molecules and have prolonged mRNA stability for these mediators.
- The absence of TTP leads to increased allergic inflammation in a skin model, suggesting that targeting TTP could be a potential therapeutic approach for managing allergies.
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