Open AccessLoperamide-induced Constipation Activates Inflammatory Signaling Pathways in the Mid Colon of SD Rats Via Complement C3 and its Receptors
Author(s) -
Yun Ju Choi,
Ji Eun Kim,
Su Jin Lee,
Jeong Eun Gong,
Miran Jang,
Jin Tae Hong,
Dae Youn Hwang
Publication year - 2022
Publication title -
current molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.567
H-Index - 105
eISSN - 1875-5666
pISSN - 1566-5240
DOI - 10.2174/1566524021666210618124220
Subject(s) - downregulation and upregulation , rhoa , pi3k/akt/mtor pathway , signal transduction , protein kinase b , receptor , phosphorylation , mapk/erk pathway , p38 mitogen activated protein kinases , kinase , cytokine , medicine , cancer research , endocrinology , pharmacology , chemistry , microbiology and biotechnology , biology , biochemistry , gene
Background: Complement component 3 (C3) receptors play an importantrole as inflammatory mediators in the innate immune system, although their mechanismswere not well studied during constipation. Objective: The aim of this study is to investigate the regulatory role of C3 and itsreceptors' downstream signaling during constipation. Methods: Alterations in the C3, C3a receptor (C3aR), and C3b receptor (C3bR)expressions, PI3K/AKT pathway, RhoA/MLC pathway, MAP kinase pathway, andinflammatory cytokine expressions were measured in the mid colon of loperamide (Lop)treated SD rats. Results: Lop treatment successfully induced constipation phenotypes, includingdecreased stool parameters and histological structure alterations. The expression levelsof C3 were significantly increased, whereas expressions of C3aR and C3bR weredecreased during Lop-induced constipation. Moreover, significant upregulation wasobserved in the phosphorylation levels of PI3K, AKT, and GSK3β in mid colons of Loptreated SD rats. The expression of RhoA and phosphorylation of MLC were alsoenhanced in the Lop treated group. Furthermore, a similar pattern was detected in theMAP kinase pathway and inflammatory cytokine expressions. Subsequent to the Loptreatment, the phosphorylation of ERK and p38, as well as the mRNA levels of NF-κB,TNF-α, IL-6 and IL-1α were remarkably increased in the mid colon. Conclusion: These results indicate that Lop-induced constipation is tightly linked to thedownregulation of C3aR and C3bR expressions, and upregulation of the C3 and C3Rsdownstream signaling pathway, including PI3K/AKT, RhoA/MLC, and MAP kinasepathways as well as inflammatory cytokine expressions in the mid colon of SD rats.