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Abstract
Protease-activated receptor 4 (PAR4) is implicated in the inhibition of visceral hyperalgesia. In the present study, the effects of PAR4 activation on visceral hypersensitivity and expression of inflammatory mediators, including interleukin-1β (IL-1β), P2RX7 purinergic receptor (P2X7), inducible nitric oxide synthase (iNOS), and tryptase, in mast cells (MCs) were investigated via in vivo and in vitro studies. The numbers of tryptase-positive MCs with extensive PAR4, P2X7, and iNOS expression were increased in the colons of visceral hyperalgesia rats compared with controls. Intracolonic administration of PAR4-activating peptide (PAR4-AP) significantly attenuated the visceral hypersensitivity to colorectal distention and reduced the iNOS, IL-1β, P2X7, and tryptase protein and mRNA levels in the colonic mucosa. Treatment of rat bone marrow MCs (BMMCs) with PAR4-AP also reduced the iNOS, IL-1β, P2X7, and tryptase protein and mRNA levels. ERK1/2 and p38 activators (t-butylhydroquinone, tBHQ, and U-46619) reversed the suppressive effect of PAR4 activation on IL-1β and iNOS expression, whereas ERK1/2 and p38 inhibitors (PD98059 and SB203580) reversed the suppressive effect of PAR4 activation on P2X7 and tryptase expression. Our results indicate that the downregulation of inflammatory mediators, including iNOS, IL-1β, P2X7, and tryptase, in MCs that are mediated by PAR4 activation could inhibit visceral hyperalgesia via the mitogen-activated protein kinase (MAPK) signal pathway.
Highlights
Accumulating evidence suggests that mast cells (MCs), especially mucosal MCs, have crucial roles in the regulation of intestinal motility, visceral sensitivity, mucosal inflammation, the permeability of the epithelial barrier, and the immune system in irritable bowel syndrome (IBS) [1, 2]
We investigated whether the activation of Protease-activated receptor 4 (PAR4) affects the mitogen-activated protein kinases (MAPK) pathway, which involved in the expressions of inducible nitric oxide (NO) synthase (iNOS), P2X7, IL-1β, and tryptase in MCs
The intracolonic administration of PAR4-activating peptide (PAR4-AP) inhibited colonic hypersensitivity and reduced the expressions of tryptase, iNOS, IL-1β, and P2X7 in the colons of the visceral hyperalgesia rats. These effects were associated with MAPK signals that were induced by PAR4 activation. These findings provide evidence that the visceral analgesia associated with PAR4-AP may involve in downregulations of tryptase, iNOS, IL-1β, and P2X7 expression via MAPK signals in MCs
Summary
Accumulating evidence suggests that mast cells (MCs), especially mucosal MCs, have crucial roles in the regulation of intestinal motility, visceral sensitivity, mucosal inflammation, the permeability of the epithelial barrier, and the immune system in irritable bowel syndrome (IBS) [1, 2]. Previous research has demonstrated that the activation of PAR4 inhibits colonic hypersensitivity through the suppression of the excitability of colonic sensory neurons and their primary afferent responses to pronociceptive mediators [8, 9]. Several studies have reported that mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 MAPK (p38), are crucial mediators of inflammation in inflammatory bowel disease (IBD) [14, 15]. We reported that PAR4 activation suppresses the Journal of Immunology Research inflammatory cytokines associated with the phosphorylation of ERK1/2 and p38 in MCs [16]. A better understanding of the role of PAR4 activation on MCs in the gut in visceral hyperalgesia is needed
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