Activation of protease-activated receptor 4 of mast cells could downregulate proinflammatory cytokines in irritable bowel syndrome

An, Shuhong; Zong, G.; Wang, Zhaojin; Shi, Juan; Du, Hongwu; Hu, Jing S.

doi:10.1136/gutjnl-2016-313504

Cited by 7 publications

(5 citation statements)

References 7 publications

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“…Moreover, protein levels of both cytokines were decreased in bladder tissue 24 hr after PAR4 treatment. It should be noted that down regulation of IL1-β and TNF-α after activation of PAR4 has been reported [42,43].…”

Section: Plos Onementioning

confidence: 94%

Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

Mahmood

et al. 2021

PLoS ONE

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Background Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo. Methodology/Principal findings We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments. Conclusions/Significance Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.

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Section: Plos Onementioning

confidence: 94%

Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

Mahmood

et al. 2021

PLoS ONE

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“…The mast cells in the intestinal tract seem to be particularly involved in the regulation of visceral hypersensitivity through PAR 4 (3,33,34). In fact, in-vitro or in-vivo activation of PAR 4 on mast cells resulted in a suppression of mRNA and protein levels of tryptase and 13 types of proinflammatory cytokines (3,35). On the contrary the role of the PAR 4 in lymphocytes is still to be clarified, however it does not seem to be involved in the modulation of nociception.…”

Section: Discussionmentioning

confidence: 99%

Proteinase Activated Receptor 4 in the Jejunum of Healthy Horses and of Horses With Epiploic Hernia

et al. 2020

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Proteinase activated receptor 4 (PAR 4) in the gastrointestinal tract is involved in the regulation of inflammation and pain pathways. The aim of the present study was to evaluate the distribution and expression of PAR 4 in the jejunum of healthy horses and in the pathologic tracts from horses undergoing surgery for herniation of the small intestine through the epiploic foramen. Eight healthy horses (Group H) and eight horses with epiploic hernia (Group EH) were included; the jejunum samples were collected at the slaughter or intraoperatively after enterectomy, respectively. To evaluate PAR 4 expression in sections of the jejunum, immunofluorescence, western blot and quantitative polymerase chain reaction (qRT-PCR) were performed. Immunohistochemistry of PAR 4 in the jejunum of the healthy horses showed that receptors are predominantly expressed in the immune cell population scattered throughout the lamina propria of the mucosa and in the submucosa. Quantitative PCR data demonstrated that PAR 4 mRNA was detectable in all of the samples analyzed without any difference between the H and the EH groups, however the PAR 4 protein level was significantly lower in the jejunums of the EH horses. In the Group EH horses, PAR 4 immunoreactivity was mainly expressed in the mast cells and was extensively distributed in the sierosa. In the lamina propria of mucosa of Group EH, leukocytes were less abundant than in Group H. In this study, the distribution and expression of PAR 4 in the jejunums of the healthy horses and in those with spontaneous occurring epiploic hernia was demonstrated.

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“…ERK1/2 and p38 activators enhanced the effects of PAR4 activation on DNMT1, HDAC2, and p16 expression, whereas ERK1/2 and p38 inhibitors reversed these effects. Several studies have supported the idea that PAR4 activation is involved in the initiation of the MAPK signal pathways [ 32 – 34 ]. Previous reports implicated the involvement of the MEK/ERK pathway in the reduction of DNMT1 expression and function [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of PAR4 Upregulates p16 through Inhibition of DNMT1 and HDAC2 Expression via MAPK Signals in Esophageal Squamous Cell Carcinoma Cells

Wang

et al. 2018

Journal of Immunology Research

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A previous study showed that a downexpression of protease-activated receptor 4 (PAR4) is associated with the development of esophageal squamous cell carcinoma (ESCC). In this study, we explored the relationship between PAR4 activation and the expression of p16, and elucidated the underlying mechanisms in PAR4 inducing the tumor suppressor role in ESCC. ESCC cell lines (EC109 and TE-1) were treated with PAR4-activating peptide (PAR4-AP). Immunohistochemistry for DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) was performed in 26 cases of ESCC tissues. We found that DNMT1 and HDAC2 immunoreactivities in ESCC were significantly higher than those in adjacent noncancerous tissues. PAR4 activation could suppress DNMT1 and HDAC2, as well as increase p16 expressions, whereas silencing PAR4 dramatically increased HDAC2 and DNMT1, as well as reduced p16 expressions. Importantly, the chromatin immunoprecipitation-PCR (ChIP-PCR) data indicated that treatment of ESCC cells with PAR4-AP remarkably suppressed DNMT1 and HDAC2 enrichments on the p16 promoter. Furthermore, we demonstrated that activation of PAR4 resulted in an increase of p38/ERK phosphorylation and activators for p38/ERK enhanced the effect of PAR4 activation on HDAC2, DNMT1, and p16 expressions, whereas p38/ERK inhibitors reversed these effects. Moreover, we found that activation of PAR4 in ESCC cells significantly inhibited cell proliferation and induced apoptosis. These findings suggest that PAR4 plays a potential tumor suppressor role in ESCC cells and represents a potential therapeutic target of this disease.

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Activation of protease-activated receptor 4 of mast cells could downregulate proinflammatory cytokines in irritable bowel syndrome

Cited by 7 publications

References 7 publications

Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

Proteinase Activated Receptor 4 in the Jejunum of Healthy Horses and of Horses With Epiploic Hernia

Activation of PAR4 Upregulates p16 through Inhibition of DNMT1 and HDAC2 Expression via MAPK Signals in Esophageal Squamous Cell Carcinoma Cells

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