Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor α, cyclooxygenase 2, and inflammatory arthritis

Phillips, Kristine; Kedersha, Nancy; Shen, Lily; Blackshear, Perry J.; Anderson, Paul J.

doi:10.1073/pnas.0400148101

Cited by 180 publications

(163 citation statements)

References 27 publications

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“…Many other mediators of immunity or inflammation are encoded by labile mRNAs that also have adenylate/uridylate-rich elements (AREs) in their 3' UTRs. COX-2, CSF2 and IL-2 genes are dysregulated in the absence of TTP (Carballo et al, 2000;Ogilvie et al, 2005;Phillips et al, 2004), and it seems likely that expression of other inflammatory mediators will also prove to be controlled by TTP. Inflammatory mRNAs can be stabilized via the phosphorylation and inactivation of TTP by MAPK-activated protein kinase 2, a kinase that is activated by p38 MAPK (Carballo et al, 2001;Chrestensen et al, 2004;Stoecklin et al, 2004).…”

Section: Tristetraprolinmentioning

confidence: 99%

Anti-inflammatory functions of glucocorticoid-induced genes

Clark

2007

Molecular and Cellular Endocrinology

237

193

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Section: Tristetraprolinmentioning

confidence: 99%

Anti-inflammatory functions of glucocorticoid-induced genes

Clark

2007

Molecular and Cellular Endocrinology

237

193

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“…The strain background is known to affect the severity of arthritis in various mouse models (21,22). However, when the DNase II −/− IFN-IR −/− B6 mice were backcrossed to BALB/c mice for five generations, they developed polyarthritis with the same kinetics as the DNase II −/− IFN-IR −/− B6 mice (Fig.…”

Section: Deletion Of the Dnase II Gene In Bone Marrow-derived Cells Cmentioning

confidence: 99%

Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

Kawane

Tanaka

Kitahara

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wildtype mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II −/− macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFα, IL-1β, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFα, IL-1β, or IL-6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFα, IL-1β, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase IInull mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis.inflammation | macrophages | apoptosis | DNase II | engulfment

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“…The mRNAs encoding TNFα and GM-CSF are stabilized in TTP-deficient mice and in cells derived from them [9,11]. Excessive levels of these cytokines in TTP knockout mice result in a severe systemic inflammatory response including arthritis, autoimmunity and myeloid hyperplasia [17,18]. On the other hand, up-regulation of TTP reduces inflammatory responses in macrophages [19].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

Cao¹,

Deterding²,

Blackshear³

2007

Expert Review of Proteomics

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Tristetraprolin (TTP) is a member of the CCCH zinc finger proteins and is an anti-inflammatory protein. Mice deficient in TTP develop a profound inflammatory syndrome with erosive arthritis, autoimmunity and myeloid hyperplasia. TTP binds to mRNA AU-rich elements with high affinity for UUAUUUAUU nucleotides and causes destabilization of those mRNA molecules. TTP is phosphorylated extensively in vivo and is a substrate for multiple protein kinases in vitro. A number of approaches have been used to identify its phosphorylation sites. This article highlights the recent progress and different approaches utilized for the identification of phosphorylation sites in mammalian TTP. Important but limited results are obtained using traditional methods including in vivo labeling, site-directed mutagenesis, phosphopeptide mapping and protein sequencing. Mass spectrometry including MALDI/MS, MALDI/MS/MS, LC/MS/MS, IMAC/MALDI/MS/MS and multidimensional protein identification technology (MudPIT) has led the way in identifying TTP phosphorylation sites. The combination of these approaches has identified multiple phosphorylation sites in mammalian TTP, some of which are predicted by motif scanning to be phosphorylated by several protein kinases. This information should provide the molecular basis for future investigation of TTP's regulatory functions in controlling pro-inflammatory cytokines.

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Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor α, cyclooxygenase 2, and inflammatory arthritis

Cited by 180 publications

References 27 publications

Anti-inflammatory functions of glucocorticoid-induced genes

Anti-inflammatory functions of glucocorticoid-induced genes

Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

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