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

Abstract

Urocortins (Ucn1–3), members of the corticotropin-releasing factor (CRF) family of neuropeptides, are emerging as potent immunomodulators. Localized, cellular expression of Ucn1 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 (CRF1 and CRF2) in regulating Ucn3 expression at baseline and during inflammation. Ucn3 mRNA and peptide were ubiquitously expressed throughout the GI tract in naïve 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 Ucn1, exogenous Ucn3 did not alter histopathological outcomes during colitis and neither did it alter levels of pro-inflammatory cytokines IL-6 and TNF-α. At baseline, colon-specific knockdown of CRF1, but not CRF2 decreased Ucn3 mRNA by 78%, whereas during colitis, Ucn3 mRNA levels increased after CRF1 knockdown. In cultured cells, co-expression of CRF1 + 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.

Sex- and corticotropin-releasing factor receptor 2- dependent actions of urocortin 1 during inflammation

“…In animal models of colitis, Ucn1, but not Ucn3, exerted anti-inflammatory effects and increased percentage of survival, as was shown previously in WT male mice after Ucn1 administration (23,42). CRF 2 Ht mice of both sexes showed 50 -60% mortality that was significantly different from controls or WT and CRF 2 KO mice, whereas CRF 2 KO mice did not differ from controls (Fig.…”

“…Although ample literature documents the prevalence of autoimmune and stress-related disorders in women, the known mechanistic basis for this sex difference is sparse. We regarded components of the CRF system as strong candidates because they play a crucial role in mediating stress and immune responses, and stress has been well documented to exacerbate IBD symptoms (7,35,42,46). Males and females have different stress responses, which, among other reasons, are due to sex steroids or differences in corticosteroid-binding globulin levels, which can modulate activation of the hypothalamic-pituitary-adrenal axis (36).…”

“…CRF 2 binds Ucn1 with 10-fold higher affinity than the other three ligands (50). Ucn1, but not Ucn2 or Ucn3, shows antiinflammatory effects during colitis in mice (23,38,42).…”

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

“…Therefore, whether the existing or newly developed CRF 1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress. Of note is also the inhibitory effects of CRF 2 receptor activation on stress-related gut motility and sensitization, as a gut stress coping system and the possible CRF 1 -CRF 2 cross talk in the colon 54,176,203 and the brain 204 that need to be taken into consideration in targeting CRF signaling for gut centric intestinal secretomotor alterations and visceral pain therapeutic purposes. CRF being pivotal in the body's response to stressful stimuli and the extensive preclinical data indicating that dysregulation of CRF-CRF 1 system is implicated in the etiology and maintenance of several stress-sensitive disorders as recently reviewed, 20,[205][206][207] a better understanding of CRF signaling is likely to provide novel insights in the otherwise challenging pathophysiology of functional gut diseases such as IBS.…”

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

“…Besides, colon specific knockdown of CRF 1 receptor, but not CRF 2 receptor altered Ucn3 expression at baseline and during inflammation in this rat model of colitis, whereas exogenous Ucn3 treatment did not ameliorate inflammation. 36 In line with the complicated effect of Ucn in the intestinal inflammation, Ucn often shows a biphasic or differential expression level depending on the disease course. In TNBS-induced colitis, Ucn2 mRNA levels markedly increased during the early phase (days 1 and 3), followed by a reduction to the basal levels during the middle phase (days 6 and 9).…”