The role of NF-κB signaling pathway in polyhexamethylene guanidine phosphate induced inflammatory response in mouse macrophage RAW264.7 cells

Kim, Ha Ryong; Shin, Dong‐Hee; Chung, Kyu Hyuck

doi:10.1016/j.toxlet.2015.01.005

Cited by 48 publications

(25 citation statements)

References 49 publications

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“…We used the passive cutaneous anaphylaxis (PCA) mouse model with IgE/Ag induction and the ovalbumin (OVA)‐induced active systemic anaphylaxis (ASA) mouse model to evaluate the inhibitory effects of tozasertib on IgE‐mediated allergic reactions (Castillo‐Courtade et al, 2015; Kee & Hong, 2017). To explore the mechanism of tozasertib effects on mast cell activation, we examined levels of inactive and activated NF‐κB p65 (p65), an important transcriptional regulator involved in mast cell degranulation (Kim, Shin, & Chung, 2015), as well as inactive and activated levels of MAPKs ([ERK, p38, and JNK; Li, Wang, & Liu, 2014). If tozasertib inhibits mast cell degranulation and allergic disease presentation effectively, it could be a candidate for repurposing into a treatment for allergic inflammatory disease.…”

Section: Introductionmentioning

confidence: 99%

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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Background and Purpose: Mast cells are important in allergic reactions. Here, we assessed the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on mast cell activation. Experimental Approach: Tozasertib effects on mast cell degranulation were determined by measuring β-hexosaminidase and histamine release and by assessing morphological changes in RBL-2H3 and mouse bone marrow-derived mast cells (BMMCs) stimulated with mouse anti-dinitrophenyl (DNP)-IgE/DNP-human serum albumin or human LAD2 cells activated with phorbol-12-myristate 13-acetate plus calcium ionophore (PMACI). Western blots were performed to detect the expression of molecules involved in NF-κB, MAPK, and Aurora kinase signalling. in vivo antiallergic effects of tozasertib were determined in the murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models. Key Results: Tozasertib treatment decreased high-affinity IgE receptor (FcεRI) or PMACI-mediated degranulation in RBL-2H3 cells and in BMMCs or LAD2 cells as shown by β-hexosaminidase or histamine levels. Similarly, tozasertib prevented morphological changes in mast cells, such as particle release and F-actin reorganization. In addition, tozasertib markedly decreased expression of phosphorylated (p)-NF-κB p65, p-Erk1/2, p-p38, and p-Aurora A/B, indicating that tozasertib can inhibit the signalling pathway mediating mast cell activation. Tozasertib attenuated IgE/Ag-induced PCA dose-dependently, as shown by reduced Evans blue staining. Similarly, tozasertib reduced body temperature levels and serum histamine levels in OVAchallenged ASA mice. Conclusion and Implications:The Aurora kinase inhibitor tozasertib suppressed mast cell activation in vitro and in vivo. Tozasertib may be a potential drug, targeting mast cell activation, to treat allergic diseases or mastocytosis.

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Section: Introductionmentioning

confidence: 99%

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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“…Therefore, the exploration of the regulatory mechanisms underlying the inflammatory response is important to elucidate the mechanism of PHMG-induced lung injury. Kim et al (2015) reported that PHMG exposure increases IL-8 expression by activating the nuclear factor kappa B (NF-κB) signaling pathway in murine RAW264.7 macrophages. However, the intracellular signaling mechanisms by which PHMG induced inflammatory cytokine production have not yet been clearly elucidated.…”

Section: Discussionmentioning

confidence: 99%

Polyhexamethylene guanidine phosphate induces IL-6 and TNF-α expression through JNK-dependent pathway in human lung epithelial cells

et al. 2018

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Polyhexamethylene guanidine phosphate (PHMG) is an antimicrobial biocide that causes severe lung injury accompanied with inflammation and subsequent fibrosis. Cytokines mediate the inflammatory response, leading to fibrosis in injured tissues. PHMG is known to induce the expression of various cytokines in vitro and in vivo. In the present study, we investigated the involvement of three MAPK subfamilies (JNK, p38 MAPK, and ERK) in PHMG-induced cytokine expression in A549 human lung epithelial cells. Our in vivo and in vitro data indicated that PHMG induced an increase in mRNA expression of IL-6 and TNF-α, and enhanced the phosphorylation of JNK, p38 MAPK, and ERK. Further, we investigated the involvement of MAPKs in PHMG-induced mRNA expression of IL-6 and TNF-α using JNK, p38 MAPK, and ERK inhibitors in A549 cells. Pre-treatment with the JNK inhibitor but not the p38 MAPK or ERK inhibitor, significantly attenuated the PHMG-induced mRNA expression of IL-6 and TNF-α. These results suggest that the activation of JNK is involved at least partially in the induction of IL-6 or TNF-α expression by PHMG in A549 cells.

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“…However, the process of inflammatory response is accompanied by activation of other signaling pathways, including nuclear factor (NF)-κB. The activation of the NF-κB signaling pathway is indicated by p65 nuclear translocation (24,25), which will be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Toxic proteins from Croton tiglium L. exert a proinflammatory effect by inducing release of proinflammatory cytokines and activating the p38-MAPK signaling pathway

Liu

et al. 2017

Molecular Medicine Reports

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The aim of the present study was to determine the toxic targets of proteins from Croton tiglium L. and to investigate the potential mechanism of their toxicity. The toxic targets were determined by oral medication and intraperitoneal injection. The median lethal dose of oral medication in mice was calculated using Bliss software (2,752.8–3,407.5 mg/kg), and that of intraperitoneal injection was 195.8–272.69 mg/kg. The results of histopathological examination demonstrated that the kidney was primarily impaired by intraperitoneal injection, with slight degeneration of renal tubular epithelial cells. As to oral medication, the digestive tract was primarily injured, which manifested as congestion, bleeding, serious edema and other symptoms. Oral administration of the proteins caused gastrointestinal edema by increasing the intestinal permeability. Severe edema was associated with the inflammatory response, therefore the association between the toxicity of the proteins and inflammation was investigated. The proinflammatory effects of the crude proteins on the release of inflammatory mediator prostaglandin E2 (PGE2) were evaluated through intraperitoneal injection and the production of proinflammatory cytokines in RAW264.7 macrophages. Maximum PGE2 was released in the mice in vivo following intraperitoneal injection with 400 mg crude protein/kg body weight. Proinflammatory cytokines in macrophages, including tumor necrosis factor-α and interleukin-1β, were produced in dose- and time-dependent manners in vitro. furthermore, the expressions of cell signaling molecules were detected by western blotting. The inflammatory response induced by crude protein in macrophages was associated with the mitogen-activated protein kinase (MAPK) signaling pathway mainly including p38-MAPK, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase 1/2/3 and the activated p38-MAPK signaling pathway. However, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinases 1–3 exhibited no significant response.

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The role of NF-κB signaling pathway in polyhexamethylene guanidine phosphate induced inflammatory response in mouse macrophage RAW264.7 cells

Cited by 48 publications

References 49 publications

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Polyhexamethylene guanidine phosphate induces IL-6 and TNF-α expression through JNK-dependent pathway in human lung epithelial cells

Toxic proteins from Croton tiglium L. exert a proinflammatory effect by inducing release of proinflammatory cytokines and activating the p38-MAPK signaling pathway

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