Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity

Saeed, Muhammad; Ng, Garrett Z.; Däbritz, Jan; Wagner, Josef; Judd, Louise M.; Han, Jia-Xi; Dhar, Poshmaal; Kirkwood, Carl D.; Sutton, Philip

doi:10.1097/mib.0000000000001045

Cited by 32 publications

(46 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These endogenous proteases are massively increased in various diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and ischemia (7,8,31,43,56). In addition, the molecular expression of both PAR1 and PAR2 are altered in patients with IBD and IBS (3,9,38,42,48). Therefore, PAR activation may affect colonic dysmotility in patients with IBD and IBS.…”

Section: Discussionmentioning

confidence: 99%

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles

Sung

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

It has been known that activation of protease-activated receptors (PARs) affects gastrointestinal motility. In this study, we tested the effects of PAR agonists on electrical and contractile responses and Ca2+ sensitization pathways in simian colonic muscles. The Simian colonic muscle was initially hyperpolarized by PAR agonists. After the transient hyperpolarization, simian colonic muscle repolarized to the control resting membrane potential (RMP) without a delayed depolarization. Apamin significantly reduced the initial hyperpolarization, suggesting that activation of small conductance Ca2+-activated K+ (SK) channels is involved in the initial hyperpolarization. In contractile experiments, PAR agonists caused an initial relaxation followed by an increase in contractions. These delayed contractile responses were not matched with the electrical responses that showed no after depolarization of the RMP. To investigate the possible involvement of Rho-associated protein kinase 2 (ROCK) pathways in the PAR effects, muscle strips were treated with ROCK inhibitors, which significantly reduced the PAR agonist-induced contractions. Furthermore, PAR agonists increased MYPT1 phosphorylation, and ROCK inhibitors completely blocked MYPT1 phosphorylation. PAR agonists alone had no effect on CPI-17 phosphorylation. In the presence of apamin, PAR agonists significantly increased CPI-17 phosphorylation, which was blocked by protein kinase C (PKC) inhibitors suggesting that Ca2+ influx is increased by apamin and is activating PKC. In conclusion, these studies show that PAR activators induce biphasic responses in simian colonic muscles. The initial inhibitory responses by PAR agonists are mainly mediated by activation of SK channels and delayed contractile responses are mainly mediated by the CPI-17 and ROCK Ca2+ sensitization pathways in simian colonic muscles. NEW & NOTEWORTHY In the present study, we found that the contractile responses of simian colonic muscles to protease-activated receptor (PAR) agonists are different from the previously reported contractile responses of murine colonic muscles. Ca2+ sensitization pathways mediate the contractile responses of simian colonic muscles to PAR agonists without affecting the membrane potential. These findings emphasize novel mechanisms of PAR agonist-induced contractions possibly related to colonic dysmotility in inflammatory bowel disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles

Sung

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…Several studies indicate an increase in proteases in in ammatory bowel disease [16]. The statistically lower activity of proteases in our patients with IBD in comparison to the control group may be a response to treatment.…”

Section: Discussionmentioning

confidence: 41%

“…Excessive or poorly controlled in ammation is the central aspect of IBD. Host factors which regulate this in ammatory response play a crucial role in the pathophysiology of IBD [16]. The activity of proteases must be strictly regulated to prevent inappropriate and often destructive proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Influence of the treatment used in inflammatory bowel disease on the level of protease activity

Dudzińska¹,

Strachecka²,

Gil-Kulik³

et al. 2020

Preprint

View full text Add to dashboard Cite

Introduction: There is growing evidence that intestinal proteases have a role in the pathogenesis of gastrointestinal inflammatory diseases. IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC), has an additional source of proteases represented by infiltrated and activated inflammatory cells. The aim of our study was to determine proteolytic system activity in patients with CD and UC. We limited the number of proteases tested by determining proteases active in acidic, neutral and alkaline pH.Material and methods: The study included 40 patients with IBD – 20 CD patients and 20 UC patients. Among the 20 CD patients, 17 were treated with aminosalicylates, 14 with azathioprine, and 4 with corticosteroids, while 8 patients were undergoing biological treatment. Among the 20 UC patients, 19 were treated with aminosalicylates, 8 with azathioprine, and 3 with corticosteroids. The optimal pH in which the enzymes were active was determined in acidic, neutral, and alkaline buffer environments. We prepared buffers of defined pH from 2.2 to 12.8, separated by 0.2 intervals and then determined proteolytic activity against substrates (gelatine, haemoglobin, ovalbumin, albumin, cytochrome C, and casein). Results: A decrease was observed in the activity of acid proteases (pH 5), alkaline proteases (pH 7), and neutral proteases (pH 7.6 and 8.6) in the groups of CD patients in remission in comparison with the active phase. In the group of patients with CD treated biologically, acid protease activity (pH 5.0) was lower than in CD patients not receiving biological treatment.Activity of neutral (pH 7.0) and alkaline (pH 7.6 and 8.6) proteases in the plasma of patients with UC in remission were lower in comparison to the active phase.Activity of acid (pH 5.0) and alkaline (8.6) protease inhibitors was higher in CD patients in the active phase in comparison to remission. In UC patients with exacerbation of the disease, the activity of alkaline (pH 8.6) protease inhibitors was increased compared to remission.Conclusions: 1. Our research may suggest that the immunomodulatory treatment used in IBD, aimed at reducing the level of leukocytes, may contribute to a reduction in protease activity.2. The decrease in the level of proteases in patients with CD and UC in remission may be a marker suggesting the patients’ response to the treatment.

show abstract

“…It is generally accepted that IL-17 is produced mainly by Th17-type lymphocytes in colon tissue of colitis 37,38 . Some studies have also pointed out that IL-17 is also largely secreted by γδT cells 39,40 or CD8 + T cells 41,42 . This study found that MA could reduce the level of IL-17 and the number of γδT17 cells in colon tissues of colitis mice, and attenuate colitis in mice.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid

Yun

Fang

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Type-17 immune response, mediated mainly by IL-17, plays a critical role in ulcerative colitis. Previously, we showed that madecassic acid (MA), the main active ingredient of Centella asiatica herbs for anti-colitis effect, ameliorated dextran sulfate sodium (DSS)-induced mouse colitis through reducing the level of IL-17. Here, we explore the effect of MA on the activation of γδT17 cells, an alternative source of IL-17 in colitis. In DSS-induced colitis mice, oral administration of MA decreased the number of γδT17 cells and attenuated the inflammation in the colon, and the anti-colitis effect of MA was significantly counteracted by redundant γδT17 cells, suggesting that the decrease in γδT17 cells is important for the anti-colitis effect of MA. In vitro, MA could inhibit the activation but not the proliferation of γδT17 cells at concentrations without evident cytotoxicity. Antibody microarray profiling showed that the inhibition of MA on the activation of γδT17 cells involved PPARγ–PTEN/Akt/GSK3β/NFAT signals. In γδT17 cells, MA could reduce the nuclear localization of NFATc1 through inhibiting Akt phosphorylation to promote GSK3β activation. Moreover, it was confirmed that MA inhibited the Akt/GSK3β/NFATc1 pathway and the activation of γδT17 cells through activating PPARγ to increase PTEN expression and phosphorylation. The correlation between activation of PPARγ, decrease in γδT17 cell number, and amelioration of colitis by MA was validated in mice with DSS-induced colitis. In summary, these findings reveal that MA inhibits the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway, which contributes to the amelioration of colitis.

show abstract

Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity

Cited by 32 publications

References 63 publications

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles

Influence of the treatment used in inflammatory bowel disease on the level of protease activity

Inhibition of the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid

Contact Info

Product

Resources

About

Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity

Cited by 32 publications

References 63 publications

The functional role of protease-activated receptors on contractile responses by activation of Ca2+sensitization pathways in simian colonic muscles

The functional role of protease-activated receptors on contractile responses by activation of Ca2+sensitization pathways in simian colonic muscles

Influence of the treatment used in inflammatory bowel disease on the level of protease activity

Inhibition of the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid

Contact Info

Product

Resources

About

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles

The functional role of protease-activated receptors on contractile responses by activation of Ca²⁺sensitization pathways in simian colonic muscles