Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis

Abstract

It is becoming increasingly evident that the urocortins (Ucns) and their receptors are involved in the initiation and development of inflammation in the gastrointestinal (GI) tract. There has not been a systematic study of the basal expression of Ucns or their receptors in the GI tract. Here, we examined basal expression of Ucn 2 and its high-affinity receptor, CRF-R2 in the rat GI tract. Ucn 2 mRNA was expressed throughout the small and large intestine. Surprisingly, CRF-R2 mRNA expression was detected in only a subset of GI regions that expressed Ucn 2. Immunohistochemical study showed that both Ucn 2 immuno-reactivity (Ucn 2-IR) and CRF-R2-IR were consistently seen in the neurons of the myenteric plexus and the nerve fibers innervating the circular muscle. By and large, Ucn 2-IR was detected in all layers, including the mucosal and the submucosal layers throughout the GI regions. In contrast, CRF-R2-IR was very low or undetectable in the mucosal layers of all regions examined. The role of Ucn 2 and CRF-R2 was then examined in a rat model of chemically-induced colitis. In the early phase of colitis, Ucn 2 mRNA levels peaked, whereas, in striking contrast, CRF-R2 mRNA expression decreased ∼2.5-fold below control levels. At the peptide level, Ucn 2-IR was specifically induced in a large population of immune cells that infiltrated the lamina propria and submucosa of the distal colon, whereas CRFR2-IR was detected in only a small fraction of infiltrated immune cells. CRF-R2-IR was dramatically reduced in the neurons of the myenteric plexus. Thus, we show, for the first time, that in the acute phase of inflammation, Ucn 2 levels are increased whereas expression levels of its only identified receptor, CRF-R2, are decreased. This suggests that Ucn 2 exerts its effects only in part via CRF-R2.

Urocortins and CRF type 2 receptor isoforms expression in the rat stomach are regulated by endotoxin: role in the modulation of delayed gastric emptying

“…Likewise, in other viscera, previous studies show that LPS injected intraperitoneally at a similar dose markedly decreased CRF 2b mRNA levels in the heart of rats and mice with a parallel time course as observed in our study (23,31). In a rat model of chemically induced colitis, a similar synchronous decrease of CRF 2 mRNA expression with the Ucn 2 peak was found in the colon (8). Mechanisms of modulation of CRF 2b expression in the stomach following intraperitoneal LPS need to be defined and may involve several indirect endocrine and immune mediators released by LPS as established in the rodent heart (2,15,31,50).…”

“…These data provide convergent pharmacological evidence for a role of peripheral Ucns/CRF 2 signaling pathways in the alterations of gastric propulsive motor function induced by acute exposure to physical/visceral stressors. However, contrary to the wealth of functional studies on the actions of Ucns and potential relevance of Ucns/CRF 2 signaling in the stomach in experimental animals and humans (3,10,33,69), little is known about the expression and regulation of Ucn ligands and CRF 2 receptors within the various gastric corpus (GC) layers compared with reports in other gut segments (7,8) or visceral organs such as the heart (31).…”

Multi-facets of Corticotropin-releasing Factor in Modulating Inflammation and Angiogenesis

“…In parallel with increased Ucn2 at the early stage of colitis, a decrease of CRF 2 receptor at this colitis phase appeared to be a compensatory mechanism in order to limit a degree of inflammatory responses in response to the increased ligand. 37 The contrasting expression pattern between a ligand and a receptor was also observed in another study. The expression of CRF 2 receptor was down-regulated in the distal/sigmoid biopsies of UC patients (mild-moderately active UC and disease in remission: also inflamed) compared to the biopsies from the healthy subjects, suggesting its involvement in the inflammatory process.…”

Estrogens downregulate urocortin 2 expression in rat uterus

“…Others and we previously demonstrated that Ucn2 is expressed in both the brain and peripheral tissues, including the lung, adrenal, uterus, ovary, and testis (Hsu & Hsueh 2001, Yamauchi et al 2005, Lee et al 2011. It has been reported that expression of Ucn2 mRNA in various tissues is controlled by stress, inflammation, and hypoxia (Tanaka et al 2003, Tao et al 2006, Chang et al 2007, Buhler et al 2009, Imperatore et al 2010, Nemoto et al 2010 and that factors involved in the regulation of Ucn2 mRNA expression are CRF, glucocorticoids, and endotoxins (Chen et al 2003(Chen et al , 2004mechanisms of Ucn2 expression in reproductive organs are not well understood.…”