Urocortin 3 expression at baseline and during inflammation in the colon: Corticotropin releasing factor receptors cross-talk

作者：Mahajan Shilpi; Liao Min; Barkan Paris; Takahashi Kazuhiro; Bhargava Aditi^*

来源：Peptides, 2014, 54: 58-66.

DOI：10.1016/j.peptides.2014.01.007

• Crohn's colitis
• Inflammation
• RNAi
• Ca2+ signaling
• MAPK

Urocortins (Ucn1-3), members of the corticotropin-releasing factor (CRF) family of neuropeptides, are emerging as potent immunomodulators. Localized, cellular expression of Ucnl and Ucn2, but not Ucn3, has been demonstrated during inflammation. Here, we investigated the role of Ucn3 in a rat model of Crohn's colitis and the relative contribution of CRF receptors (CRF] and CRF2) in regulating Ucn3 expression at baseline and during inflammation. Ucn3 mRNA and peptide were ubiquitously expressed throughout the GI tract in naive rats. Ucn3 immunoreactivity was seen in epithelial cells and myenteric neurons. On day 1 of colitis, Ucn3 mRNA levels decreased by 80% and did not recover to baseline even by day 9. Next, we ascertained pro- or anti-inflammatory actions of Ucn3 during colitis. Surprisingly, unlike observed anti-inflammatory actions of Ucnl, exogenous Ucn3 did not alter histopathological outcomes during colitis and neither did it alter levels of pro-inflammatory cytokines IL-6 and TNF-alpha. At baseline, colon-specific knockdown of CRF], but not CRF2 decreased Ucn3 mRNA by 78%, whereas during colitis, Ucn3 mRNA levels increased after CRF] knockdown. In cultured cells, co-expression of CRF] + CRF2 attenuated Ucn3-stimulated intracellular Ca2+ peak by 48% as compared to cells expressing CRF2 alone. Phosphorylation of p38 kinase increased by 250% during colitis and was significantly attenuated after Ucn3 administration. Thus, our results suggest that a balanced and coordinated expression of CRF receptors is required for proper regulation of Ucn3 at baseline and during inflammation.

• 出版日期2014-4