Role of glycine <scp>N</scp>‐methyltransferase in experimental ulcerative colitis

Chou, Wen Yueh; Zhao, Jin; Chen, Yi Ming Arthur; Lee, Kuan I.; Su, Kuo‐Hui; Shyue, Song Kun; Lee, Tzong‐Shyuan

doi:10.1111/jgh.12434

Cited by 6 publications

(9 citation statements)

References 31 publications

(78 reference statements)

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“…In addition, Gomez-Santos et al reported that functional loss of GNMT augmented NK cell-mediated inflammation and exacerbated endotoxin-induced acute liver injury (13). Moreover, absence of GNMT exacerbated the deregulation of the inflammatory response in an experimental ulcerative colitis model (12). Collectively, these evidences suggested that GNMT exerts protective antiinflammatory effects in acute inflammation models and during activation of innate immune responses.…”

Section: Discussionmentioning

confidence: 98%

“…In Gnmt and apolipoprotein E double knockout mice, GNMT deficiency modulated the functions of macrophages and exacerbated the pathogenesis of hyperlipidemia, inflammation and atherosclerosis, indicating that GNMT regulates the inflammatory responses by modulating the function of macrophages (11). Moreover, GNMT deficiency increased the susceptibility to dextran sulfate sodium (DSS)-induced colitis in mice (12). Natural killer (NK) cells from Gnmt -/mice were activated spontaneously, expressed more tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) and had stronger cytotoxic activity, suggesting that they contributed to a proinflammatory environment in the liver (13).…”

Section: Introductionmentioning

confidence: 99%

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Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

Li¹,

Lin

Chu

et al. 2014

Mol Med

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Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt-/mice developed hepatocellular carcinoma, we hypothesized that Gnmt-/mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt-/mice. Pathological examination of the spinal cords revealed that Gnmt-/mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt-/than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG 35-55-induced Gnmt-/mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt-/-CD4 + T cells via an IL-2-and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4 + T cells was much milder than in those with wild-type CD4 + T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4 + T-cell functions.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

Li¹,

Lin

Chu

et al. 2014

Mol Med

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“…Leukocyte infiltration and cytokine production as indicators of inflammatory status are crucial in determining the stages of certain inflammatory diseases [ 14 , 24 ]. These key inflammatory events can trigger the process of tissue remodeling and fibrosis such as cell proliferation and apoptosis, epithelial-mesenchymal transition (MET), fibroblast activation, and extracellular matrix deposition [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, oxidative stress is known to be highly associated with the regulation of inflammation in a variety of inflammatory diseases [ 14 , 18 ]. This notion was further supported by our findings that the levels of superoxide anion radical and hydrogen peroxide in UUO kidneys were increased in WT mice, which was reduced in UUO kidneys of sEH −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Deletion of Soluble Epoxide Hydrolase Attenuates Inflammation and Fibrosis in Experimental Obstructive Nephropathy

Chiang

Lee²,

Tarng

et al. 2015

Mediators of Inflammation

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Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) and sEH deficient (sEH −/−) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated in sEH −/− mice with the exception of glomerulosclerosis. Moreover, sEH −/− mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase, collagen 1A1, and α-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys of sEH −/− mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases.

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Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis

et al. 2014

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Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.

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Role of glycine N‐methyltransferase in experimental ulcerative colitis

Abstract: Collectively, our findings suggest that GNMT may be a crucial molecule in the pathogenesis of DSS-induced colitis. This finding may provide new information for a potential therapeutic target in treating IBD.

Cited by 6 publications

References 31 publications

Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

Genetic Deletion of Soluble Epoxide Hydrolase Attenuates Inflammation and Fibrosis in Experimental Obstructive Nephropathy

Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis

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