Downregulation of iNOS, IL-1β, and P2X7 Expression in Mast Cells via Activation of PAR4 Contributes to the Inhibition of Visceral Hyperalgesia in Rats

• Published in: Journal of immunology research Vol. 2018; no. 2018; pp. 1 - 9
• Main Authors: Wang, Ming, An, Shuhong, Niu, Hao, Hao, Yanli, Wang, Zhaojin
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2018; Hindawi; Hindawi Limited; Wiley
• Subjects: Activation; Animals; Animals, Newborn; Anti-Inflammatory Agents - therapeutic use; Bone marrow; Cells, Cultured; Colon - physiology; Colon - surgery; Cytokines; Disease Models, Animal; Down-Regulation; Extracellular signal-regulated kinase; Gastroenterology; Humans; Hyperalgesia; Hyperalgesia - genetics; Hyperalgesia - therapy; Hypersensitivity; IL-1β; Immunology; Inflammation; Inhibition; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Irritable bowel syndrome; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; Mast cells; Mast Cells - physiology; mRNA; Mucosa; Nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Oligopeptides - therapeutic use; Pain; Pain perception; Peptides; Protein kinase; Proteins; Rats; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Receptors, Thrombin - metabolism; Rodents; Roles; Sensation; t-Butylhydroquinone; Tryptase; Tryptases - genetics; Tryptases - metabolism; Viscera - pathology; Viscera - surgery
• ISSN: 2314-8861; 2314-7156
• DOI: 10.1155/2018/3256908

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.