Activation of PRMT1 and PRMT5 mediates hypoxia- and ischemia-induced apoptosis in human lung epithelial cells and the lung of miniature pigs: The role of p38 and JNK mitogen-activated protein kinases

Lim, Seul Ki; Jeong, Yong Wun; Kim, Dong Il; Park, Min Jung; Choi, Joo Hee; Kim, Se Un; Kang, Seong Soo; Han, Ho Jae; Park, Soo Hyun

doi:10.1016/j.bbrc.2013.09.136

Cited by 29 publications

(20 citation statements)

References 19 publications

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“…TCR signaling cascades include the NFAT, Erk1/2, p38 and JNK MAPK. Interestingly, inhibitors of the p38 and JNK-MAPK, but not ERK1/2, pathway have been shown to inhibit hypoxia-induced up-regulation of PRMT5 in lung epithelial cells (65). While future studies will be required to clarify the extent to which these pathways affect PRMT5 up-regulation in T cells, NF-κB appears to play a major role in TCR-induced PRMT5 expression in human Th1, but not Th2, cells.…”

Section: Discussionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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In the autoimmune disease multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the Protein Arginine Methyl Transferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. Here, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently up-regulated during maximal proliferation of both mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in Delayed Type Hypersensitivity (DTH) and clinical disease in Experimental Autoimmune Encephalomyelitis (EAE) mouse models. These data implicate PRMT5 in regulation of adaptive memory T helper cell responses and suggest PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease.

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Section: Discussionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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“…In a previous study, we revealed that increased PRMT1 expression is associated with cellular apoptosis in lung epithelial cells and retinal pigment epithelial cells [ 25 , 26 ]. However, the roles of PRMT1 in apoptosis in other cells, especially non-tumor cells, were barely explored.…”

Section: Discussionmentioning

confidence: 99%

Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress

Park

Han

Kim

2017

IJMS

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Lipotoxicity-induced mesangial cell apoptosis is implicated in the exacerbation of diabetic nephropathy (DN). Protein arginine methyltransferases (PRMTs) have been known to regulate a variety of biological functions. Recently, it was reported that PRMT1 expression is increased in proximal tubule cells under diabetic conditions. However, their roles in mesangial cells remain unexplored. Thus, we examined the pathophysiological roles of PRMTs in mesangial cell apoptosis. Treatment with palmitate, which mimics cellular lipotoxicity, induced mesangial cell apoptosis via protein kinase RNA-like endoplasmic reticulum kinase (PERK) and ATF6-mediated endoplasmic reticulum (ER) stress signaling. Palmitate treatment increased PRMT1 expression and activity in mesangial cells as well. Moreover, palmitate-induced ER stress activation and mesangial cell apoptosis was diminished by PRMT1 knockdown. In the mice study, high fat diet-induced glomerular apoptosis was attenuated in PRMT1 haploinsufficient mice. Together, these results provide evidence that lipotoxicity-induced PRMT1 expression promotes ER stress-mediated mesangial cell apoptosis. Strategies to regulate PRMT1 expression or activity could be used to prevent the exacerbation of DN.

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“…Hence, any dysregulation of PRMT1 expression and/or activity may have a great impact on lung homeostasis [13]. Abnormal PRMT1 expression has recently been implicated in the pathogenesis of asthma and pulmonary hypertension by influencing the eosinophil infiltration of the airways [20] and hypoxia-inducible factor (HIF)-dependent responses, respectively [25]. Our study demonstrates, for the first time, that PRMT1 protein expression is enhanced in IPF lungs and that this may have potential consequences for the migratory properties of the cells.…”

Section: Discussionmentioning

confidence: 99%

Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis

Zakrzewicz

Didiášová

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Activation of PRMT1 and PRMT5 mediates hypoxia- and ischemia-induced apoptosis in human lung epithelial cells and the lung of miniature pigs: The role of p38 and JNK mitogen-activated protein kinases

Cited by 29 publications

References 19 publications

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress

Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis

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