Role of calcitonin receptor-like receptor in colonic motility and inflammation
Role of calcitonin receptor-like receptor in colonic motility and inflammation
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DOI：
10.1152/ajpgi.00464.2006
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发表时间：
2007-07-01
影响因子：
4.5
通讯作者：
Bhargava, Aditi
中科院分区：
文献类型：
--
作者：
Clifton, Matthew S.;Hoy, Julia J.;Bhargava, Aditi
降钙素基因相关肽（CGRP）介导神经源性炎症并调节肠动力。CGRP受体是降钙素受体样受体（CGRP）和受体相关修饰蛋白1的异源二聚体。我们使用RNA干扰来阐明结肠动力和炎症中的特异性作用。在两个位点向结肠壁内注射抗Escherichia coli（dsEscherichia coli）的双链RNA（dsRNA），在注射dsRNA后1天内引起结肠中Escherichia coli的空间和时间下调。敲除持续7 - 9天，并且敲除的效果扩散到注射部位近端和远端2cm处，而对照dsRNA注射不影响cDNAs表达。测量离体结肠肌段的等长收缩显示，在对照dsRNA注射大鼠中，CGRP完全废除收缩并降低静息肌张力，而在dsCLR注射大鼠中，CGRP降低肌张力，但不同幅度的慢波收缩持续存在。在三硝基苯磺酸诱导的结肠炎中，与盐水或对照dsRNA注射的大鼠相比，敲低BMP 3的大鼠显示出显著更大程度的水肿和坏死。促炎细胞因子TNF-α和IL-6的水平显着上调三硝基苯磺酸治疗。TNF-α mRNA水平进一步增加，而IL-6水平不变。因此，本研究表明，CGRP是一种功能性受体。
Calcitonin gene-related peptide (CGRP) mediates neurogenic inflammation and modulates intestinal motility. The CGRP receptor is a heterodimer of calcitonin receptor-like receptor (CLR) and receptor-associated modifying protein 1. We used RNA interference to elucidate the specific role of CLR in colonic motility and inflammation. Intramural injection of double-stranded RNA (dsRNA) against CLR (dsCLR) into the colonic wall at two sites caused the spatial and temporal downregulation of CLR in the colon within 1 day of dsRNA injection. Knockdown of CLR persisted for 7 - 9 days, and the effect of knockdown spread to similar to 2 cm proximal and distal to the injection sites, whereas control dsRNA injection did not affect CLR expression. Measurement of isometric contractions of isolated colonic muscle segments revealed that in control dsRNA-injected rats, CGRP abrogated contractions entirely and decreased resting muscular tone, whereas in dsCLR-injected rats, CGRP decreased muscle tone but slow-wave contractions of varying amplitude persisted. In trinitrobenzene sulfonic acid-induced colitis, rats with knockdown of CLR displayed a significantly greater degree of edema and necrosis than saline- or control dsRNA-injected rats. Levels of the proinflammatory cytokines TNF-alpha and IL-6 were markedly upregulated by trinitrobenzene sulfonic acid treatment. TNF-alpha mRNA levels were further increased in CLR knockdown rats, whereas levels of IL-6 were unaltered. Thus this study demonstrates that CLR is a functional receptor for CGRP.