Skip to main content

Advertisement

SpringerLink
Log in

Expression of corticotropin-releasing factor and urocortins in the normal and Schistosoma mansoni-infected mouse ileum

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Corticotropin-releasing factor (CRF) and urocortins (UCNs) are important ligands in the CRF signaling pathways, which are most known for their role in the hypothalamic–pituitary–adrenal stress axis. However, peripheral CRF signaling also has profound effects on gastrointestinal functions. Although the murine animal model is highly relevant for the exploration of this complexly balanced pathway via genetic manipulation, little is known about the expression of CRF and UCNs in the mouse intestine. This study aims to investigate the cellular localization of CRF and UCNs in the ileum and to explore whether and how this cellular expression is altered in conditions of intestinal Schistosoma mansoni-induced inflammation. The results show a distinct expression pattern for the different CRF receptor ligands in the ileum. CRF was located in nerve fibers and stromal cells. All UCNs were expressed in polymorphonuclear leukocytes. Furthermore, UCN2 and UCN3 were found in the musculature. During acute schistosomiasis, UCN1 showed an increased immunoreactivity in blood vessels and UCN3 was de novo expressed mainly in submucous neurons. Typical features of S. mansoni-inflamed ileum, such as nerve fiber sprouting, muscle layer thickening and granuloma formation thus all have an impact on the CRF signaling pathways. In conclusion, we outline for the first time the expression of CRF signaling ligands in the mouse ileum; our results point to important changes of this signaling system in S. mansoni-induced intestinal inflammation, which warrants further functional investigation with specific focus on CRF2, given the exclusive binding of UCN2 and UCN3 to this receptor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Avula LR, Buckinx R, Alpaerts K, Costagliola A, Adriaensen D, Van Nassauw L, Timmermans J-P (2011) The effect of inflammation on the expression and distribution of the MAS-related gene receptors MrgE and MrgF in the murine ileum. Histochem Cell Biol 136:569–585

    Article  CAS  PubMed  Google Scholar 

  • Avula LR, Knapen D, Buckinx R, Vergauwen L, Adriaensen D, Van Nassauw L, Timmermans J-P (2012) Whole-genome microarray analysis and functional characterization reveal distinct gene expression profiles and patterns in two mouse models of ileal inflammation. BMC Genomics 13:377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barreau F, Cartier C, Leveque M, Ferrier L, Moriez R, Laroute V, Rosztoczy A, Fioramonti J, Bueno L (2007) Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin-releasing factor and nerve growth factor interplay. J Physiol 580:347–356

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bogers J, Moreels T, De Man J, Vrolix G, Jacobs W, Pelckmans P, van Marck E (2000) Schistosoma mansoni infection causing diffuse enteric inflammation and damage of the enteric nervous system in the mouse small intestine. Neurogastroenterol Motil 12:431–440

    Article  CAS  PubMed  Google Scholar 

  • Böhm M, Zmijewski MA, Wasiewicz T, Straub RH, Raap U, Luger TA, Slominski A (2012) KU812 basophils express urocortin, CRH-R, MC1R and steroidogenic enzymes and secrete progesterone. Exp Dermatol 21:541–543

    Article  PubMed  Google Scholar 

  • Brown SL, Riehl TE, Walker MR, Geske MJ, Doherty JM, Stenson WF, Stappenbeck TS (2007) Myd88-dependent positioning of Ptgs2- expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest 117(1):258–269

  • Buckinx R, Adriaensen D, Van Nassauw L, Timmermans J-P (2011) Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract. Front Neurosci 5:54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chang J, Hoy JJ, Idumalla PS, Clifton MS, Pecoraro NC, Bhargava A (2007) Urocortin 2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis. Peptides 28:1453–1460

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chatzaki E, Anton PA, Million M, Lambropoulo M, Constantinidis T, Kolios G, Taché Y, Grigoriadis DE (2013) Corticotropin-releasing factor receptor subtype 2 in human colonis mucosa: down-regulation in ulcerative colitis. World J Gastroenterol 19(9):1416–1423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen A, Blount A, Vaughan J, Brar B, Vale W (2004) Urocortin II gene is highly expressed in mouse skin and skeletal muscle tissues: localization, basal expression in corticotropin-releasing factor receptor (CRFR) 1- and CRFR2-null mice, and regulation by glucocorticoids. Endocrinology 145:2445–2457

    Article  CAS  PubMed  Google Scholar 

  • La Fleur SE, Wick EC, Idumalla PS, Grady EF, Bhargava A (2005) Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum. Proc Natl Acad Sci U S A 102:7647–7652

    Article  PubMed Central  PubMed  Google Scholar 

  • Harada S, Imaki T, Naruse M, Chikada N, Nakajima K, Demura H (1999) Urocortin mRNA is expressed in the enteric nervous system of the rat. Neurosci Lett 267:125–128

    Article  CAS  PubMed  Google Scholar 

  • Hoffman J, Baritaki S, Ruiz J, Sideri A, Pothoulakis C (2014) Corticotropin-releasing hormone receptor 2 signaling promotes mucosal healing following colitis. Neurogastroenterol Motil 26(Supplement S1):8

    Google Scholar 

  • Höllt V, Garzón J, Schulz R, Herz A (1984) Corticotropin-releasing factor is excitatory in the guinea-pig ileum and activates an opioid mechanism in this tissue. Eur J Pharmacol 101:165–166

    Article  PubMed  Google Scholar 

  • Hsu SY, Hsueh AJ (2001) Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 7:605–611

    Article  CAS  PubMed  Google Scholar 

  • De Jonge F, Van Nassauw L, Adriaensen D, Van Meir F, Miller HRP, Van Marck E, Timmermans J-P (2003) Effect of intestinal inflammation on capsaicin-sensitive afferents in the ileum of Schistosoma mansoni-infected mice. Histochem Cell Biol 119:477–484

    Article  PubMed  Google Scholar 

  • Kiank C, Taché Y, Larauche M (2010) Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin-releasing factor receptors. Brain Behav Immun 24:41–48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kokkotou E, Torres D, Moss AC, O′Brien M, Grigoriadis DE, Karalis K, Pothoulakis C (2006) Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses. J Immunol 177:3355–3361

    Article  CAS  PubMed  Google Scholar 

  • Kozicz T, Arimura A (2002) Distribution of urocortin in the rat′s gastrointestinal tract and its colocalization with tyrosine hydroxylase. Peptides 23:515–521

    Article  CAS  PubMed  Google Scholar 

  • Larauche M, Kiank C, Tache Y (2009) Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications. J Physiol Pharmacol 60(Suppl 7):33–46

    PubMed Central  PubMed  Google Scholar 

  • Lázár Z, Benkó R, Bölcskei K, Rumbus Z, Wolf M, Holzer P, Maggi C, Barthó L (2003) Actions of endothelin and corticotropin releasing factor in the guinea-pig ileum: no evidence for an interaction with capsaicin-sensitive neurons. Neuropeptides 37:220–232

    Article  PubMed  Google Scholar 

  • Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW (2001) Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci U S A 98:7570–7575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu S, Gao N, Hu H-Z, Wang X, Wang G-D, Fang X, Gao X, Xia Y, Wood JD (2006) Distribution and chemical coding of corticotropin-releasing factor-immunoreactive neurons in the guinea pig enteric nervous system. J Comp Neurol 494:63–74

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu S, Gao X, Gao N, Wang X, Fang X, Hu H-Z, Wang G-D, Xia Y, Wood JD (2005) Expression of type 1 corticotropin-releasing factor receptor in the guinea pig enteric nervous system. J Comp Neurol 481:284–298

    Article  CAS  PubMed  Google Scholar 

  • Llewellyn-Smith IJ, Costa M, Furness JB (1985) Light and electron microscopic immunocytochemistry of the same nerves from whole mount preparations. J Histochem Cytochem 33:857–866

    Article  CAS  PubMed  Google Scholar 

  • Mahajan S, Min L, Barkan P, Takahashi K, Bhargava A (2014) Urocortin 3 expression at baseline and during inflammation in the colon: Corticotropin releasing factor receptors cross-talk. Peptides 54:58–66

    Article  CAS  PubMed  Google Scholar 

  • Mongardi Fantaguzzi C, Thacker M, Chiocchetti R, Furness JB (2009) Identification of neuron types in the submucosal ganglia of the mouse ileum. Cell Tissue Res 336:179–189

    Article  CAS  PubMed  Google Scholar 

  • Moss AC, Anton P, Savidge T, Newman P, Cheifetz AS, Gay J, Paraschos S, Winter MW, Moyer MP, Karalis K, Kokkotou E, Pothoulakis C (2007) Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2alpha. Gut 56:1210–1217

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Muramatsu Y, Fukushima K, Iino K, Totsune K, Takahashi K, Suzuki T, Hirasawa G, Takeyama J, Ito M, Nose M, Tashiro A, Hongo M, Oki Y, Nagura H, Sasano H (2000) Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa. Peptides 21:1799–1809

    Article  CAS  PubMed  Google Scholar 

  • Overman EL, Rivier JE, Moeser AJ (2012) CRF induces intestinal epithelial barrier injury via the release of mast cell proteases and TNF-α. PLoS ONE 7:e39935

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Perrin M, Donaldson C, Chen R, Blount A, Berggren T, Bilezikjian L, Sawchenko P, Vale W (1995) Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc Natl Acad Sci U S A 92:2969–2973

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Porcher C, Juhem A, Peinnequin A, Sinniger V, Bonaz B (2005) Expression and effects of metabotropic CRF1 and CRF2 receptors in rat small intestine. Am J Physiol Gastrointest Liver Physiol 288:G1091–G1103

    Article  CAS  PubMed  Google Scholar 

  • Qu Z-D, Thacker M, Castelucci P, Bagyánszki M, Epstein ML, Furness JB (2008) Immunohistochemical analysis of neuron types in the mouse small intestine. Cell Tissue Res 334:147–161

    Article  CAS  PubMed  Google Scholar 

  • Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE (2001) Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci U S A 98:2843–2848

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Saito-Nakaya K, Hasegawa R, Nagura Y, Ito H, Fukudo S (2008) Corticotropin-releasing hormone receptor 1 antagonist blocks colonic hypersensitivity induced by a combination of inflammation and repetitive colorectal distension. Neurogastroenterol Motil 20:1147–1156

    Article  CAS  PubMed  Google Scholar 

  • Sand E, Themner-Persson A, Ekblad E (2011) Corticotropin releasing factor-distribution in rat intestine and role in neuroprotection. Regul Pept 166:68–75

    Article  CAS  PubMed  Google Scholar 

  • Santos J, Alonso C, Vicario M, Ramos L, Lobo B, Malagelada J-R (2008) Neuropharmacology of stress-induced mucosal inflammation: implications for inflammatory bowel disease and irritable bowel syndrome. Curr Mol Med 8:258–273

    Article  CAS  PubMed  Google Scholar 

  • Saruta M, Takahashi K, Suzuki T, Torii A, Kawakami M, Sasano H (2004) Urocortin 1 in colonic mucosa in patients with ulcerative colitis. J Clin Endocrinol Metab 89:5352–5361

    Article  CAS  PubMed  Google Scholar 

  • Saruta M, Takahashi K, Suzuki T, Fukuda T, Akira T, Sasano H (2005) Urocortin 3/stresscopin in human colon: possible modulators of gastrointestinal function during stressful conditions. Peptides 26:1196–1206

    Article  CAS  PubMed  Google Scholar 

  • Wallon C, Yang PC, Keita AV, Ericson AC, McKay DM, Sherman PM, Perdue MH, Söderholm JD (2008) Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro. Gut 57:50–58

    Article  CAS  PubMed  Google Scholar 

  • Wlk M, Wang CC, Venihaki M, Liu J, Zhao D, Anton PM, Mykoniatis A, Pan A, Zacks J, Karalis K, Pothoulakis C (2002) Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum. Gastroenterology 123:505–515

    Article  CAS  PubMed  Google Scholar 

  • Yolles TK, Moore DV, Meleney HE (1949) Post-cercarial development of Schistosoma mansoni in the rabbit and hamster after intraperitoneal and percutaneous infection. J Parasitol 35:276–294

    Article  CAS  PubMed  Google Scholar 

  • Yuan P-Q, Wu SV, Elliott J, Anton PA, Chatzaki E, Million M, Taché Y (2012) Expression of corticotropin releasing factor receptor type 1 (CRF1) in the human gastrointestinal tract and upregulation in the colonic mucosa in patients with ulcerative colitis. Peptides 38(1):62–69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant of the Flemish Organization for Scientific Research (FWO G.0179.08 N). We would like to thank the staff of the Laboratory of Cell Biology and Histology for their technical assistance, with special gratitude to Gunther Vrolix for the maintenance of the S. mansoni life cycle. We appreciate the help of Danny Vindevogel, who linguistically proofread our manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium

    Roeland Buckinx, Maria Bagyanszki, Leela Rani Avula, Dirk Adriaensen, Luc Van Nassauw & Jean-Pierre Timmermans

  2. Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

    Maria Bagyanszki

  3. Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Luc Van Nassauw

Authors
  1. Roeland Buckinx
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Bagyanszki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leela Rani Avula
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dirk Adriaensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luc Van Nassauw
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Pierre Timmermans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean-Pierre Timmermans.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary figure

(GIF 196 kb)

High resolution image (TIFF 2484 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buckinx, R., Bagyanszki, M., Avula, L.R. et al. Expression of corticotropin-releasing factor and urocortins in the normal and Schistosoma mansoni-infected mouse ileum. Cell Tissue Res 359, 453–463 (2015). https://doi.org/10.1007/s00441-014-2012-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-014-2012-8

Keywords

Search

Navigation