Z Gastroenterol 2006; 44(9): 985-990
DOI: 10.1055/s-2006-926968
Übersicht

© Karl Demeter Verlag im Georg Thieme Verlag KG Stuttgart · New York

Die enterische Glia und neurotrophe Faktoren

The Enteric Glia and Neurotrophic FactorsG. von Boyen1 , M. Steinkamp1
  • 1Klinik für Innere Medizin I, Ärztlicher Direktor Prof. Dr. Adler, Universität Ulm
Further Information

Publication History

Manuskript eingetroffen: 16.5.2006

Manuskript akzeptiert: 3.7.2006

Publication Date:
15 September 2006 (online)

Zusammenfassung

Die enterische Glia stellt eine essenzielle Zellentität im Gastrointestinaltrakt dar. Ohne die glial fibrillary acidic protein (GFAP) exprimierende Glia ist ein Überleben des Organismus nicht möglich. Dies wurde in einem Tiermodell demonstriert. Bei Verlust der enterischen GFAP-positiven glialen Zellen sterben die Tiere in kürzester Zeit an einer schweren hämorrhagischen Darmentzündung. Die Mechanismen der enterischen Glia, diese letal endende Darmentzündung zu verhindern und die Darmhomöostase aufrechtzuerhalten, sind noch unbekannt. Es verdichten sich jedoch die Hinweise, dass die Sekretion neurotropher Faktoren durch die enterische Glia ein Bestandteil der glialen Homöostaseregulation zu sein scheint. Hierbei spielt die Sekretion von glia cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF) und transforming growth factor-β1 (TGF-β1) einen wichtigen Einfluss auf die epitheliale Homöostase, und die Sekretion von Endothelinen könnte an der intestinalen Vasoregulation beteiligt sein. Diese neuen Aspekte der glialen Funktion im Darm legen mögliche Therapieansätze bei Erkrankungen wie M. Crohn und dem Reizdarmsyndrom nahe.

Abstract

Enteric glia cells (EGCs) play an important role in the maintenance of tissue integrity in the gastrointestinal tract. Thus, genetic ablation of glial fibrillary acidic protein (GFAP)-positive EGCs in mice induced fatal haemorrhagic jejuno-ileitis and led to death within a few days. The exact mechanisms of EGC to contribute to gut homeostasis remain enigmatic. Several lines of evidence implicate that the secretion of neurotrophic factors by EGC may be a part of the glial regulation of gut homoeostasis. The secretion of glia cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and transforming growth factor-β (TGF-β) contributes to the maintenance of epithelial integrity and the secretion of endothelins might be involved in vasoregulation. These new aspects of intestinal glial functions implicate new therapeutic strategies for diseases like Crohn’s disease and irritable bowel syndrome.

Literatur

  • 1 Bush T G, Savidge T C, Freeman T C. et al . Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice.  Cell. 1998;  93 189-201
  • 2 Cornet A, Savidge T C, Cabarrocas J. et al . Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn’s disease?.  Proc Natl Acad Sci USA. 2001;  98 13306-13311
  • 3 Wedel T, Roblick U, Gleiss J. et al . Organization of the enteric nervous system in the human colon demonstrated by wholemount immunohistochemistry with special reference to the submucous plexus.  Ann Anat. 1999;  181 327-337
  • 4 Krammer H J, Kuhnel W. Topography of the enteric nervous system in Peyer’s patches of the porcine small intestine.  Cell Tissue Res. 1993;  272 267-272
  • 5 Gabella G. Ultrastructure of the nerve plexuses of the mammalian intestine: the enteric glial cells.  Neuroscience. 1981;  6 425-436
  • 6 Gershon M D, Rothman T P. Enteric glia.  Glia. 1991;  4 195-204
  • 7 Bjorklund H, Dahl D, Seiger A. Neurofilament and glial fibrillary acid protein-related immunoreactivity in rodent enteric nervous system.  Neuroscience. 1984;  12 277-287
  • 8 Cabarrocas J, Savidge T, Liblau R S. Role of enteric glial cells in inflammatory bowel disease.  Glia. 2003;  41 81-93
  • 9 Endo Y, Kobayashi S. A scanning electron microscope study on the autonomic groundplexus in the lamina propria mucosae of the guinea-pig small intestine.  Arch Histol Jpn. 1987;  50 243-250
  • 10 Mestres P, Diener M, Rummel W. Electron microscopy of the mucosal plexus of the rat colon.  Acta Anat. 1992;  143 275-282
  • 11 Gershon M D, Bursztajn S. Properties of the enteric nervous system: limitation of access of intravascular macromolecules to the myenteric plexus and muscularis externa.  J Comp Neurol. 1978;  180 467-488
  • 12 Erde S M, Sherman D, Gershon M D. Morphology and serotonergic innervation of physiologically identified cells of the guinea pig’s myenteric plexus.  J Neurosci. 1985;  5 617-633
  • 13 Bush T G. Enteric glial cells. An upstream target for induction of necrotizing enterocolitis and Crohn’s disease?.  Bioessays. 2002;  24 130-140
  • 14 Jessen K R, Mirsky R. Glial cells in the enteric nervous system contain glial fibrillary acidic protein.  Nature. 1980;  286 736-737
  • 15 Ferri G L, Probert L, Cocchia D. et al . Evidence for the presence of S-100 protein in the glial component of the human enteric nervous system.  Nature. 1982;  297 409-410
  • 16 Jessen K R, Mirsky R. Astrocyte-like glia in the peripheral nervous system: an immunohistochemical study of enteric glia.  J Neurosci. 1983;  3 2206-2218
  • 17 Bannerman P G, Mirsky R, Jessen K R. et al . Light microscopic immunolocalization of laminin, type IV collagen, nidogen, heparan sulphate proteoglycan and fibronectin in the enteric nervous system of rat and guinea pig.  J Neurocytol. 1986;  15 733-743
  • 18 Von Boyen G B, Reinshagen M, Steinkamp M. et al . Gut inflammation modulated by the enteric nervous system and neurotrophic factors.  Scand J Gastroenterol. 2002;  37 621-625
  • 19 Von Boyen G B, Reinshagen M, Steinkamp M. et al . Enteric nervous plasticity and development: dependence on neurotrophic factors.  J Gastroenterol. 2002;  37 583-588
  • 20 Ruhl A. Glial cells in the gut.  Neurogastroenterol Motil. 2005;  17 777-790
  • 21 Von Boyen G B, Steinkamp M, Reinshagen M. et al . Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia.  Gut. 2004;  53 222-228
  • 22 Von Boyen G B, Steinkamp M, Geerling I. et al . Proinflammatory Cytokines Induce Neurotrophic Factor Expression in Enteric Glia: A Key to the Regulation of Epithelial Apoptosis in Crohn’s Disease.  Inflamm Bowel Dis. 2006;  24 346-354
  • 23 Bar K J, Facer P, Williams N S. et al . Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung’s disease.  Gastroenterology. 1997;  112 1381-1385
  • 24 di Mola F F, Friess H, Zhu Z W. et al . Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease.  Gut. 2000;  46 670-679
  • 25 Von Boyen G B, Steinkamp M, Reinshagen M. et al . Nerve Growth Factor (NGF) secretion in cultured enteric glia cells is modulated by proinflammatory cytokines.  J Neuroendocrinol. Manuskript in press; 
  • 26 Neunlist M, Aubert P, Bonnaud S. et al . Enteric glia inhibits intestinal epithelial cell proliferation partly through a TGF-{beta}1-dependent pathway.  Am J Physiol Gastrointest Liver Physiol. 2006, Epub ahead of print; 
  • 27 Steinkamp M, Geerling I, Seufferlein T. et al . Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells.  Gastroenterology. 2003;  124 1748-1757
  • 28 Ogura Y, Bonen D K, Inohara N. et al . A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.  Nature. 2001;  411 603-606
  • 29 Reinshagen M, Rohm H, Steinkamp M. et al . Protective role of neurotrophins in experimental inflammation of the rat gut.  Gastroenterology. 2000;  119 368-376
  • 30 Barreau F, Cartier C, Ferrier L. et al . Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats.  Gastroenterology. 2004;  127 524-534
  • 31 Lindsay R M, Harmar A J. Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons.  Nature. 1989;  337 362-364
  • 32 Collins S M, Vallance B, Barbara G. et al . Putative inflammatory and immunological mechanisms in functional bowel disorders.  Baillieres Best Pract Res Clin Gastroenterol. 1999;  13 429-436
  • 33 Chang L, Munakata J, Mayer E A. et al . Perceptual responses in patients with inflammatory and functional bowel disease.  Gut. 2000;  47 497-505
  • 34 Lembo T, Naliboff B, Munakata J. et al . Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome.  Am J Gastroenterol. 1999;  94 1320-1326
  • 35 Chadwick V S, Chen W, Shu D. et al . Activation of the mucosal immune system in irritable bowel syndrome.  Gastroenterology. 2002;  122 1778-1783
  • 36 Dunlop S P, Hebden J, Campbell E. et al . Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.  Am J Gastroenterol. 2006;  101 1288-1294
  • 37 Coulie B, Szarka L A, Camilleri M. et al . Recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans.  Gastroenterology. 2000;  119 41-50
  • 38 Grider J R, Piland B E, Gulick M A. et al . Brain-derived neurotrophic factor augments peristalsis by augmenting 5-HT and calcitonin gene-related peptide release.  Gastroenterology. 2006;  130 771-780
  • 39 Shanahan F. Crohn’s disease.  Lancet. 2002;  359 62-69
  • 40 Strater J, Wellisch I, Riedl S. et al . CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis.  Gastroenterology. 1997;  113 160-167
  • 41 Allescher H D. Further extension of the brain-gut axis?.  Neurogastroenterol Motil. 2003;  15 243
  • 42 Ehrenreich H, Schilling L. New developments in the understanding of cerebral vasoregulation and vasospasm: the endothelin-nitric oxide network.  Cleve Clin J Med. 1995;  62 105-116
  • 43 Lerman A, Hildebrand jr FL, Aarhus L L. et al . Endothelin has biological actions at pathophysiological concentrations.  Circulation. 1991;  83 1808-1814
  • 44 Ruhl A. Glial regulation of neuronal plasticity in the gut: implications for clinicians.  Gut. 2006;  55 600-602
  • 45 Ruhl A, Franzke S, Collins S M. et al . Interleukin-6 expression and regulation in rat enteric glial cells.  Am J Physiol Gastrointest Liver Physiol. 2001;  280 G1163-G1171
  • 46 Mottet C, Uhlig H H, Powrie F. Cutting edge: cure of colitis by CD4 +CD25 + regulatory T cells.  J Immunol. 2003;  170 3939-3943
  • 47 Liu H, Hu B, Xu D. et al . CD4 +CD25 + regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4.  J Immunol. 2003;  171 5012-5017
  • 48 Denning T L, Qi H, Konig R. et al . CD4 + Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions between CD4 and class II MHC.  J Immunol. 2003;  171 2279-2286
  • 49 Tozawa K, Hanai H, Sugimoto K. et al . Evidence for the critical role of interleukin-12 but not interferon-gamma in the pathogenesis of experimental colitis in mice.  J Gastroenterol Hepatol. 2003;  18 578-587
  • 50 Nielsen O H, Kirman I, Rudiger N. et al . Upregulation of interleukin-12 and -17 in active inflammatory bowel disease.  Scand J Gastroenterol. 2003;  38 180-185
  • 51 Watanabe T, Kitani A, Murray P J. et al . NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.  Nat Immunol. 2004;  5 800-808
  • 52 Maeda S, Hsu L C, Liu H. et al . Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing.  Science. 2005;  307 734-738
  • 53 Tamboli C P, Neut C, Desreumaux P. et al . Dysbiosis in inflammatory bowel disease.  Gut. 2004;  53 1-4
  • 54 Schmid M, Fellermann K, Wehkamp J. et al . The role of defensins in the pathogenesis of chronic-inflammatory bowel disease.  Z Gastroenterol. 2004;  42 333-338
  • 55 Wehkamp J, Harder J, Weichenthal M. et al . NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression.  Gut. 2004;  53 1658-1664
  • 56 Weinstock J V, Summers R, Elliott D E. Helminths and harmony.  Gut. 2004;  53 7-9
  • 57 Becker C, Wirtz S, Blessing M. et al . Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells.  J Clin Invest. 2003;  112 693-706
  • 58 Quigley E M. Changing face of irritable bowel syndrome.  World J Gastroenterol. 2006;  12 1-5
  • 59 Levy R L, Jones K R, Whitehead W E. et al . Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology.  Gastroenterology. 2001;  121 799-804
  • 60 Quigley E M. Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: biological markers or epiphenomenon.  Gastroenterol Clin North Am. 2005;  34 221-233
  • 61 Quigley E M. From comic relief to real understanding; how intestinal gas causes symptoms.  Gut. 2003;  52 1659-1661
  • 62 Camilleri M. Probiotics and irritable bowel syndrome: rationale, putative mechanisms, and evidence of clinical efficacy.  J Clin Gastroenterol. 2006;  40 264-269
  • 63 Barbara G, Stanghellini V, de Giorgio R. et al . Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.  Gastroenterology. 2004;  126 693-702
  • 64 Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open?.  Am J Gastroenterol. 2006;  101 1295-1298
  • 65 Furness J B, Costa M. Types of nerves in the enteric nervous system.  Neuroscience. 1980;  5 1-20

Dr. Georg von Boyen

Abteilung Innere Medizin I, Universität Ulm

Robert-Koch-Str. 8

89081 Ulm

Phone: ++49/7 31/50 04 03 26

Fax: ++49/7 31/50 04 03 31

Email: georg.boyen@medizin.uni-ulm.de

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