Non-Hematopoietic β-Arrestin1 Confers Protection Against Experimental Colitis

Lee, Taehyung; Lee, Eun-Hee; Arrollo, David; Lucas, Peter C.; Parameswaran, Narayanan

doi:10.1002/jcp.25216

Cited by 10 publications

(13 citation statements)

References 62 publications

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“…However, the role of β-arr1 in intestinal epithelial cell apoptosis in colitis remains controversial. A recent study demonstrated that β-arr1 deficiency protected mice from experimental colitis 53 , while another study showed that β-arr1 in the non-hematopoietic compartment (likely epithelial cells) is protective during colitis 54 . The most recent studies have shown that β-arr1 exerts a protective effect in epithelial cells and stem cells 55 , 56 .…”

Section: Discussionmentioning

confidence: 99%

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

Peng

Tan

et al. 2017

Sci Rep

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COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE2 treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2 in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC.

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Section: Discussionmentioning

confidence: 99%

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

Peng

Tan

et al. 2017

Sci Rep

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“…DSS-induced colitis model. Colitis was induced in mice with DSS as previously described (15,16,32). In brief, mice were administered DSS (3.5-4.25% wt/vol) in their drinking water for the indicated times.…”

Section: Methodsmentioning

confidence: 99%

G protein-coupled receptor kinase-2-deficient mice are protected from dextran sodium sulfate-induced acute colitis

Steury

Kang

Lee

et al. 2018

Physiological Genomics

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G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase and plays a key role in different disease processes. Previously, we showed that GRK2 knockdown enhances wound healing in colonic epithelial cells. Therefore, we hypothesized that ablation of GRK2 would protect mice from dextran sodium sulfate (DSS)-induced acute colitis. To test this, we administered DSS to wild-type (GRK2) and GRK2 heterozygous (GRK) mice in their drinking water for 7 days. As predicted, GRK2 mice were protected from colitis as demonstrated by decreased weight loss (20% loss in GRK2 vs. 11% loss in GRK2). lower disease activity index (GRK2 9.1 vs GRK2 4.1), and increased colon lengths (GRK2 4.7 cm vs GRK2 5.3 cm). To examine the mechanisms by which GRK2 mice are protected from colitis, we investigated expression of inflammatory genes in the colon as well as immune cell profiles in colonic lamina propria, mesenteric lymph node, and in bone marrow. Our results did not reveal differences in immune cell profiles between the two genotypes. However, expression of inflammatory genes was significantly decreased in DSS-treated GRK2 mice compared with GRK2. To understand the mechanisms, we generated myeloid-specific GRK2 knockout mice and subjected them to DSS-induced colitis. Similar to whole body GRK2 heterozygous knockout mice, myeloid-specific knockout of GRK2 was sufficient for the protection from DSS-induced colitis. Together our results indicate that deficiency of GRK2 protects mice from DSS-induced colitis and further suggests that the mechanism of this effect is likely via GRK2 regulation of inflammatory genes in the myeloid cells.

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“…38 Recent studies have shown that the regulation of β-arrestin varies on different MAPK signaling pathways. [39][40][41] Since the MAPK pathway is the key mediator of UC inflammatory signals, and β-arrestin regulates MAPK, we speculate that the β-arrestin-MAPK pathway is involved in the regulation of PCS in UC. Our study showed that the inhibition of EPCR expression induced by TNF-α or IL-6 was reversed by SB203580 and SP600125.…”

Section: Discussionmentioning

confidence: 93%

IgG plasma cells initiate changes in the protein Csystem inmouse ulcerative colitis through CD14+CD64+ macrophage activation

Lin

Wang

et al. 2019

Adv Clin Exp Med

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Non-Hematopoietic β-Arrestin1 Confers Protection Against Experimental Colitis

Cited by 10 publications

References 62 publications

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

G protein-coupled receptor kinase-2-deficient mice are protected from dextran sodium sulfate-induced acute colitis

IgG plasma cells initiate changes in the protein Csystem inmouse ulcerative colitis through CD14+CD64+ macrophage activation

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