Peroxisome proliferator‐activated receptor γ 2 mutation may cause a subset of ulcerative colitis

Aoyagi, Yo; Nagata, Satoru; Kudo, Toshifumi; Fujii, Tôru; Wada, Mariko; Chiba, Yukihide; Ohtsuka, Yoshikazu; Yamashiro, Yuichiro; Shimizu, Toshiaki; Ohkusa, Toshifumi

doi:10.1111/j.1442-200x.2010.03195.x

Cited by 29 publications

(22 citation statements)

References 43 publications

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“…As a representative negative regulator of the PRR-linked signals, the peroxisome proliferatoractivated receptor g (PPARg) mediates immune tolerance to bacteria-stimulated inflammation associated with colitis (10)(11)(12). Genetic ablation of PPARg is observed in patients with ulcerative colitis, which is associated with severe chronic inflammatory outcomes (10). As another regulatory transcription factor, activating transcription factor 3 (ATF3) is induced as part of the negative feedback loop that modulates PRR-stimulated inflammatory responses (13)(14)(15).…”

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confidence: 99%

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confidence: 99%

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Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

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In response to excessive nucleotide-binding oligomerization domain–containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

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confidence: 99%

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confidence: 99%

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Park

Hun

Choi

et al. 2013

The Journal of Immunology

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“…Although TLRs signal transmit through the MyD88-dependent or -independent pathway, previous studies have indicated a significant role of the TLR-MyD88 pathway on IBD (15,25). Aoyagi et al have reported that mRNA levels of MyD88, TLR-4 and NF-κB p65 are significantly increased in colonic mucosa of UC patients (26). It has also been reported that the Myd88 protein level is increased in the colonic mucosa of non-treated UC and this increase is suppressed by azathioprine treatment (15).…”

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confidence: 99%

“…In addition, there is no evidence regarding the function of rs7744. However, there may be a possibility of overexpressing the MyD88 protein in the rs7744 minor allele variants, considering overexpression of mRNA and protein levels of MyD88 in UC patients (15,26). There are binding sites of miR-150-3p and miR-1236 of 100 bp around rs7744.…”

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confidence: 99%

The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis

Matsunaga

Tahara

Shiroeda

et al. 2013

Molecular Medicine Reports

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Abstract. Toll-like receptor activation intitially recruits the myeloid differentiation primary response gene (88) (MyD88) protein. A polymorphism *1244 A>G (rs7744) in the 3'-untranslated region of MyD88 has been identified. In the present study, the association of this polymorphism with ulcerative colitis (UC) was investigated. The population studied comprised 922 individuals, including patients with UC (UC cases) and without (controls). Genotyping of rs7744 was performed by PCR single-strand conformation polymorphism and the rs7744 G allele frequencies in the controls and UC cases were 32.8 and 43.5%, respectively (P<0.0001). The results showed that the genotype frequency of the AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls (P=0.0012 for both groups). The rs7744 minor allele variants were significantly associated with susceptibility to UC as indicated by dominant and recessive genetic models. The minor allele variants were associated with an increased risk for UC in the male individuals but not the female individuals. The rs7744 was also associated with a non-continuous phenotype of UC and steroid unused/independent UC. This minor allele homozygote was associated with the disease severity of UC, hospitalization and response to steroid treatment. The results of the present study provided evidence that MyD88 polymorphism rs7744 was significantly associated with the development of UC and that this polymorphism may be associated with the response to treatment therapies for

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“…28 Recent studies have shown a significant association between deficiency of PPAR and IBD. 48 In addition, activation of PPAR could attenuate the inflammation in the gut. 49 These results suggest that colonic PPAR may be a promising therapeutic target in patients suffering from IBD.…”

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Modulation of Colitis-associated Colon Tumorigenesis by Baicalein and Betaine

Kim¹,

Sung²,

Chung³

et al. 2014

Journal of Cancer Prevention

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In this review, we will summarize the current understanding of modulation of colitis-associated colon tumorigenesis by two natural products, baicalein and betaine, which have anti-inflammatory activities. Baicalein and betaine have been shown to provide various health benefits to organism in many ways. Baicalein is a phenolic flavonoid derived originally from the root of Scutellaria baicalensis Georgi. From ancient times, baicalein has widely been used in oriental medicines as an anti-inflammatory and anti-cancer therapy. Betaine, trimethylglycine, is an essential biochemical molecule of the methionine/homocysteine cycle and is synthesized by conversion of choline. Betaine is an important human nutrient obtained from various foods including sugar beet and lycium. Betaine has provided various health benefits including disease prevention. However, the action mechanisms of their activity remain poorly understood. Recent studies reported the effects of baicalein and betaine on cytotoxicity against colon cancer cells and chemically induced colitis-associated colon tumorigenesis in mice. Administrations of baicalein and betaine containing diets significantly inhibited the incidence of tumors and hyperplasia with down-regulation of inflammation. Therefore, baicalein and betaine might be applicable to the prevention of inflammation-associated colon carcinogenesis.

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Peroxisome proliferator‐activated receptor γ 2 mutation may cause a subset of ulcerative colitis

Abstract: These findings suggested that imbalances between TLRs and PPARγ in response to luminal bacteria could lead to colonic inflammation in some UC patients. Alternative explanations will be needed for the onset of the rest of UC and CD.

Cited by 29 publications

References 43 publications

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis

Modulation of Colitis-associated Colon Tumorigenesis by Baicalein and Betaine

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