Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2

Moss, Alan C.; Anton, Pauline M.; Savidge, Tor; Newman, Paul; Cheifetz, Adam S.; Paraschos, Sophia; Winter, Michael; Moyer, Mary Pat; Karalis, Katia; Kokkotou, Efi; Pothoulakis, Charalabos

doi:10.1136/gut.2006.110668

Cited by 61 publications

(61 citation statements)

References 49 publications

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“…An interesting possibility is via cytokine, driven NF-B-dependent mechanisms as shown in Fig. 6B, and previously described for substance P (36) and CRH (34) receptors. An important question relates to the mechanisms by which MCH-MCHR1 interactions mediate proinflammatory responses in the intestinal mucosa, including colonic epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies on the role of additional neuropeptides such as substance P, neurotensin, and members of the corticotropinreleasing hormone (CRH) family of peptides in intestinal inflammation demonstrated that receptors for these molecules are expressed in intestinal epithelial cells and their expression is increased during the course of inflammation (30)(31)(32)(33)(34). Hence, to examine epithelial cell expression of MCH and its receptors, we used a laser capture microdissection (LCM) approach to isolate colonic epithelial cells from cryopreserved surgical specimens obtained from patients with IBD and controls (35).…”

Section: Mch Functional Receptors Are Expressed In Colonocytesmentioning

confidence: 99%

See 1 more Smart Citation

Melanin-concentrating hormone as a mediator of intestinal inflammation

Kokkotou¹,

Moss²,

Torres³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Melanin-concentrating hormone (MCH) is expressed primarily in the hypothalamus and has a positive impact on feeding behavior and energy balance. Although MCH is expressed in the gastrointestinal tract, its role in this system remains elusive. We demonstrate that, compared to wild type, mice genetically deficient in MCH had substantially reduced local inflammatory responses in a mouse model of experimental colitis induced by intracolonic administration of 2,4,6 trinitrobenzene sulfonic acid (TNBS). Likewise, mice receiving treatments with an anti-MCH antibody, either prophylactically or after the establishment of colitis, developed attenuated TNBS-associated colonic inflammation and survived longer. Consistent with a potential role of MCH in intestinal pathology, we detected increased colonic expression of MCH and its receptor in patients with inflammatory bowel disease. Moreover, we found that human colonic epithelial cells express functional MCH receptors, the activation of which induces IL-8 expression. Taken together, these results clearly implicate MCH in inflammatory processes in the intestine and perhaps elsewhere.experimental colitis ͉ IL-8 ͉ inflammatory bowel disease ͉ neuropeptides ͉ MCH deficient mice M elanin-concentrating hormone (MCH) is a 17-to 19-aa cyclic neuropeptide conserved from fish to human (1) and predominantly localized in the brain (2). Several pharmacological and genetic studies revealed a role for this peptide in the regulation of feeding behavior and energy expenditure toward a positive energy balance (3-5). More recent studies extended the physiological functions of MCH as a broad regulator of cognitive and autonomic aspects related to rewarding behaviors (6, 7). Outside the brain, MCH is localized in the pancreas (8), skin (9), and gastrointestinal tract (10). It has been also found in tissular and circulating immune cells (11)(12)(13)(14). However, the physiological role of MCH in these peripheral tissues has yet to be established.In humans, two G-protein-coupled receptors for MCH have been identified, MCHR1 (also known as SLC1 or GPR24) (15-18) and MCHR2 (19-21), whereas rodents express only MCHR1. In the rodent brain, MCHR1 is expressed in areas important for feeding, learning and motivated behavior, integration of sensory and gustatory inputs, autonomic control, and arousal (22, 23). MCHR1 mRNA is also expressed in the thyroid, kidney, adipose tissue, lung, testes, and tongue (23), whereas functional MCHR1 is also present in lymphocytes (12,14), insulin-producing cell lines (24), and mouse and human pancreatic islets (8).Several neuropeptides that are part of the neuroendocrine system exhibit important immunomodulatory effects and mediate inflammation in various organs, including the intestine (25, 26). There is little evidence to indicate expression of MCHR of either type in the intestine of animals or humans, and the role of MCH in inflammatory responses in the gut or elsewhere has not been evaluated. Based on these considerations and because MCH is also expressed in immune c...

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Section: Discussionmentioning

confidence: 99%

Section: Mch Functional Receptors Are Expressed In Colonocytesmentioning

confidence: 99%

Melanin-concentrating hormone as a mediator of intestinal inflammation

Kokkotou¹,

Moss²,

Torres³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been reported that urocortin increases vascular permeability in the lung (21) and skin (25), and that both CRFR1 and CRFR2 may be involved in defining mucosal permeability in the intestine (20). There are data demonstrating urocortin and CRF pathwaymediated mast cell activation (25), and involvement in the modulation of inflammation (26), but a definitive mechanistic explanation for effects on vascular permeability has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Hao

Huang

Cleman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The corticotropin-releasing factor (CRF) receptor CRFR2 is expressed widely in peripheral tissues and in the vasculature, although its functional roles in those tissues have only recently begun to be elucidated. Previously we found that genetic deletion of CRFR2 resulted in profound postnatal hypervascularization in mice, characterized by both an increase in total vessel number and a dramatic increase in vessel diameter. These data strongly suggested that ligands for CRFR2 act to limit tissue vascularity, perhaps as a counterbalance to factors that promote neovascularization. Urocortin 2 (Ucn2) is a specific ligand for the CRFR2. We hypothesized that activation of CRFR2 by Ucn2 might thus suppress tumor vascularization and consequently limit tumor growth. Here, we show that viral-mediated expression of Ucn2 strikingly inhibits the growth and vascularization of Lewis Lung Carcinoma Cell (LLCC) tumors in vivo. Further, we found that this effect on tumor growth inhibition was independent of whether exposure to Ucn2 occurred before or after establishment of measurable tumors. In vitro, Ucn2 directly inhibited the proliferation of LLCC, suggesting that the tumor-suppressing effects of CRFR2 activation involve a dual mechanism of both a direct inhibition of tumor cell cycling and the suppression of tumor vascularization. These results establish that Ucn2 inhibits tumor growth, suggesting a potential therapeutic role for CRFR2 ligands in clinical malignancies.anti-angiogenic ͉ cancer ͉ CRF ͉ peptide ͉ CRFR2

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“…In addition, a recent study showed that the expression of Ucn II mRNA was increased in mucosal samples of patients with inflammatory bowel disease, and in human intestinal xenografts following exposure to Clostridium difficile toxin A (Moss et al 2007), an activator of NF-kB (Jefferson et al 1999), indicating that the regulation of Ucn II may be involved in the NF-kB pathway. Our present results showed that LPS, Ang II, and H 2 O 2 Figure 5 Dose-dependent expression of Ucn I and Ucn II mRNA by LPS (Ucn I (A), Ucn II (E)) and by TNF-a (Ucn I (B), Ucn II (F)) and expression of Ucn I mRNA by Ang II (C) and H 2 O 2 (D) in HL-1 cardiomyocytes at 3 h. Expression of Ucn I mRNA following stimulation by LPS, TNF-a, Ang II, and H 2 O 2 , and Ucn II mRNA by TNF-a were generally increased in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes

Ikeda¹,

Tojo²,

Inada³

et al. 2009

Journal of Molecular Endocrinology

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Despite our knowledge on the regulation of urocortin (Ucn) I and its related peptides in the heart, the possible involvement of cardiovascular stress substances, such as cytokines or angiotensin II (Ang II), on this regulation remains to be fully elucidated. We therefore evaluated the potential role of cardiovascular stress substances on the regulation of the Ucn-corticotropin-releasing hormone (CRH) receptor system in HL-1 cardiomyocytes using a Ucn I-specific RIA, conventional reverse transcription-PCR (RT-PCR) and quantitative real-time RT-PCR. Ucn I mRNA levels were shown to be up-regulated by lipopolysaccarides (LPS), tumor necrosis factor-a (TNF-a), Ang II, H 2 O 2 , and pyrrolidinedithiocarbamate (PDTC). The LPS-and Ang II-induced increase in Ucn I mRNA levels was abolished by tempol. In addition, the secretion of Ucn I from HL-1 cardiomyocytes was stimulated by LPS and TNF-a. On the contrary, Ucn II mRNA was increased by TNF-a alone and Ang II with tempol, and the TNF-a-induced increase in Ucn II mRNA was abolished by erythromycin and PDTC. These results suggested that Ucn I mRNA may be up-regulated by oxidative stress, whereas Ucn II mRNA may be up-regulated by the activated nuclear factor-kB, i.e. inflammatory stress. CRH-R2 mRNA may be negatively regulated by the increase in expression of Ucn I and/or Ucn II mRNA. In conclusion, the Ucn-CRH receptor system may be regulated by two major forms of cardiac stresses, i.e. oxidative and inflammatory stress, and may play a critical role in cardiac stress adaptation in heart diseases.

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Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2

Cited by 61 publications

References 49 publications

Melanin-concentrating hormone as a mediator of intestinal inflammation

Melanin-concentrating hormone as a mediator of intestinal inflammation

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes

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