Urocortins and CRF receptor type 2 variants in the male rat colon: gene expression and regulation by endotoxin and anti-inflammatory effect

Urocortins (Ucns) 1, 2, and 3 and corticotropin-releasing factor receptor 2 (CRF₂) mRNA are prominently expressed in various layers of the upper gut. We tested whether Ucns and CRF₂ variants are also expressed in the different layers of the rat colon, regulated by LPS (100 μg/kg ip) and play a modulatory role in the colonic immune response to LPS. Transcripts of Ucns and CRF_2b, the most common isoform in the periphery, were detected in all laser microdissected layers, including myenteric neurons. LPS increased the mRNA level of Ucn 1, Ucn 2, and Ucn 3 and decreased that of CRF_2b in both the colonic mucosa and submucosa + muscle (S+M) layers at 2, 6, and 9 h after injection with a return to basal at 24 h. In addition, CRF_2a, another variant more prominent in the brain, and a novel truncated splice variant CRF_2a-3 mRNA were detected in all segments of the large intestine. LPS reciprocally regulated the colonic expression of these CRF₂ variants by decreasing both CRF_2a and CRF_2b, while increasing CRF_2a-3 in the mucosa and S+M. The CRF₂ antagonist astressin₂-B further enhanced LPS-induced increase of mRNA level of interleukin (IL)-1β, TNF-α, and inducible nitric oxide synthase in S+M layers and IL-1β in the mucosa and evoked TNF-α expression in the mucosa. These data indicate that Ucns/CRF₂ variants are widely expressed in all colonic layers and reciprocally regulated by LPS. CRF₂ signaling dampens the CD14/TLR4-mediated acute inflammatory response to Gram-negative bacteria in the colon.

From: Yuan, P.-Q., Wu, S. V., Pothoulakis, C., Tache, Y. http://ajpgi.physiology.org/cgi/content/abstract/310/6/G387?rss=1