Zinc Finger Protein Tristetraprolin Interacts with CCL3 mRNA and Regulates Tissue Inflammation

Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2011; 187(5):2696-701. DOI: 10.4049/jimmunol.1101149
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "For atherosclerotic plaque quantification, the whole aorta or aortic root at the base of the heart was dissected and stained with Sudan IV or Oil Red O solution, respectively, as previously described [13, 19]. The base of the heart was fixed in 10 % formalin, frozen in OCT Compound (Tissue Teck), cross-sections cut at the level of the aortic valves, and stained with either hematoxylin and eosin (H&E) for histology or Oil Red O for plaque area measurements. "
    [Show abstract] [Hide abstract] ABSTRACT: Large population studies have shown that living at higher altitudes, which lowers ambient oxygen exposure, is associated with reduced cardiovascular disease mortality. However, hypoxia has also been reported to promote atherosclerosis by worsening lipid metabolism and inflammation. We sought to address these disparate reports by reducing the ambient oxygen exposure of ApoE−/− mice. We observed that long-term adaptation to 10 % O2 (equivalent to oxygen content at ∼5000 m), compared to 21 % O2 (room air at sea level), resulted in a marked decrease in aortic atherosclerosis in ApoE−/− mice. This effect was associated with increased expression of the anti-inflammatory cytokine interleukin-10 (IL-10), known to be anti-atherogenic and regulated by hypoxia-inducible transcription factor-1α (HIF-1α). Supporting these observations, ApoE−/− mice that were deficient in IL-10 (IL10−/− ApoE−/− double knockout) failed to show reduced atherosclerosis in 10 % oxygen. Our study reveals a specific mechanism that can help explain the decreased prevalence of ischemic heart disease in populations living at high altitudes and identifies ambient oxygen exposure as a potential factor that could be modulated to alter pathogenesis. Key messages Chronic low ambient oxygen exposure decreases atherosclerosis in mice. Anti-inflammatory cytokine IL-10 levels are increased by low ambient O2. This is consistent with the established role of HIF-1α in IL10 transactivation. Absence of IL-10 results in the loss of the anti-atherosclerosis effect of low O2. This mechanism may contribute to decreased atherosclerosis at high altitudes.
    Preview · Article · Feb 2016 · Journal of Molecular Medicine
  • Source
    • "Also, in rheumatoid arthritis upregulated TTP is found in cells involved in pathogenesis [52] and may be a marker of severe disease [53], in part because of production stimulated by the TTP target TNF. Although the complete absence of TTP (knockout mice) is associated with uncontrolled inflammatory responses [20,54-56] and TTP influences cytokine levels in cell culture models, there are conflicting reports on whether TTP and TNF levels are correlated in rheumatoid arthritis patient samples [34,53]. Exposure of mouse brain to hypertonic insult resulted in upregulation of both TTP and TNF [57]. "
    [Show abstract] [Hide abstract] ABSTRACT: The RNA-binding protein tristetraprolin (TTP) participates in normal post-transcriptional control of cytokine and chemokine gene expression, dysregulation of which contributes to the HIV-associated neurocognitive disorders. Transcriptional and post-transcriptional regulation of TTP has been described, including regulation by microRNA-29a. In the simian immunodeficiency virus (SIV) model of HIV CNS disease, control of cytokine/chemokine expression coincides with the end of acute phase infection. This control is lost during progression to disease. In this study, we assessed TTP regulation and association with cytokine regulation in the brain during SIV infection. Quantitation of TTP expression over the course of SIV infection revealed downregulation of TTP during acute infection, maintenance of relatively low levels during asymptomatic phase, and increased expression only during late-stage CNS disease, particularly in association with severe disease. The ability of miR-29a to regulate TTP was confirmed, and evidence for additional miRNA targeters of TTP was found. However, increased miR-29a expression in brain was not found to be significantly negatively correlated with TTP. Similarly, increased TTP during late-stage disease was not associated with lower cytokine expression. TTP expression is regulated during SIV infection of the CNS. The lack of significant negative correlation of miR-29a and TTP expression levels suggests that while miR-29a may contribute to TTP regulation, additional factors are involved. Reduced TTP expression during acute infection is consistent with increased cytokine production during this phase of infection, but the increases in TTP observed during late-stage infection were insufficient to halt runaway cytokine levels. While antisense inhibitors of the post-transcriptional targeters of TTP identified here could conceivably be used further to augment TTP regulation of cytokines, it is possible that high levels of TTP are undesirable. Additional research is needed to characterize members of the miRNA/TTP/cytokine regulatory network and identify nodes that may be best targeted therapeutically to ameliorate the effects of chronic inflammation in retrovirus-associated CNS disease.
    Full-text · Article · Sep 2013 · Molecular Brain
  • Source
    • "Tristetraprolin (TTP; encoded by Zfp36) is one of the best-characterized ARE-binding protein . TTP limits the production of several TLR-induced cytokines , including TNF, IL6, GM-CSF, and CCL3 (Lai et al., 1999; Carballo et al., 2000; Kang et al., 2011; Van Tubergen et al., 2011). Recently, transcriptome analyses indicate that out of 546 LPS-inducible transcripts in macrophages, 138 were found to be unstable. "
    [Show abstract] [Hide abstract] ABSTRACT: Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.
    Full-text · Article · Aug 2013 · Journal of Experimental Medicine
Show more