Abstract
Background
Dysregulation of immune responses in inflammatory bowel diseases (IBD) results in intestinal inflammation and vascular injury while exacerbating systemic disease. CD39 is an ectonucleotidase, expressed by T regulatory cells and dendritic cells, that hydrolyzes extracellular nucleotides to modify those cellular immune responses implicated in IBD. Genetic polymorphisms of CD39 have been linked to Crohn’s disease while gene deletion in mice exacerbates dextran sodium sulphate-induced colitis.
Aim
The aim of this study was to test how global deletion of CD39 in mice impacts other models of experimental colitis.
Methods
Colitis was induced in CD39-null and -wt mice, using trinitrobenzene sulfonic acid (TNBS, 125 mg/kg) administered intrarectally. Oxazolone colitis (1.5% oxazolone in 50% alcohol) was induced in comparable groups. Morphology, clinical and molecular parameters, and FACS analyses of lamina propria mononuclear cells (LPMC) were examined in CD39-null mice. CD39 expression was analyzed in human IBD biopsies.
Results
Paradoxically, TNBS colitis in CD39-null mice was characterized by improved survival, favorable clinical scores, and decreased MPO activity, when compared to wt mice (P < 0.05). LPMC from TNBS colitis contained significantly increased amounts of T-cells (CD3+ and CD4+) and TNF-α mRNA expression were increased over those in CD39 null mice (P < 0.05). In contrast, oxazolone treated CD39-null and wt mice had comparable outcomes. In both ulcerative colitis and Crohn’s disease, CD39 is present at high levels in intestinal tissue biopsies.
Conclusions
TNBS colitis was attenuated in CD39-null mice whereas oxazolone-induced colitis was not impacted. Impaired adaptive cellular immune reactivity in the CD39-null environment appears protective in hapten-mediated Th1-type colitis. CD39 is expressed at high levels in clinical IBD tissues.
Similar content being viewed by others
References
Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity. 2002;17:629–638.
Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998;115:182–205.
Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–1517.
Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44:534–541.
Buell G, Lewis C, Collo G, North RA, Surprenant A. An antagonist-insensitive P2X receptor expressed in epithelia and brain. Embo J. 1996;15:55–62.
Burnstock G, Knight GE. Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol. 2004;240:31–304.
Dranoff JA, Kruglov EA, Robson SC, Braun N, Zimmermann H, Sevigny J. The ecto-nucleoside triphosphate diphosphohydrolase NTPDase2/CD39L1 is expressed in a novel functional compartment within the liver. Hepatology. 2002;36:1135–1144.
Di Virgilio F, Solini A. P2 receptors: new potential players in atherosclerosis. Br J Pharmacol. 2002;135:831–842.
Hou M, Harden TK, Kuhn CM, et al. UDP acts as a growth factor for vascular smooth muscle cells by activation of P2Y(6) receptors. Am J Physiol Heart Circ Physiol. 2002;282:H784–792.
Atarashi K, Nishimura J, Shima T, et al. ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008;455:808–812.
Enjyoji K, Sevigny J, Lin Y, et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med. 1999;5:1010–1017.
Robson SEK, Goepfert C, Imai M, et al. Modulation of extracellular nucleotide-mediated signaling by CD39/nucleoside triphosphate diphosphohydrolase-1. Drug Dev Res. 2001;53:193–207.
Kaczmarek E, Koziak K, Sevigny J, et al. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem. 1996;271:33116–33122.
Sevigny J, Sundberg C, Braun N, et al. Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation. Blood. 2002;99:2801–2809.
Kansas GS, Tedder TF. Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway. J Immunol. 1991;147:4094–4102.
Vrij AA, Rijken J, van Wersch JW, Stockbrugger RW. Coagulation and fibrinolysis in inflammatory bowel disease and in giant cell arteritis. Pathophysiol Haemost Thromb. 2003;33:75–83.
Mizumoto N, Kumamoto T, Robson SC, et al. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med. 2002;8:358–365.
Takashima A, Mummert M, Kitajima T, Matsue H. New technologies to prevent and treat contact hypersensitivity responses. Ann NY Acad Sci. 2000;919:205–213.
Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257–1265.
Kunzli BM, Nuhn P, Enjyoji K, et al. Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice. Gastroenterology. 2008;134:292–305.
Matsuura M, Okazaki K, Nishio A, et al. Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis. Gastroenterology. 2005;128:975–986.
Boirivant M, Fuss IJ, Chu A, Strober W. Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med. 1998;188:1929–1939.
Kunzli BM, Berberat PO, Giese T, et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. Am J Physiol Gastrointest Liver Physiol. 2007;292:G223–230.
De Jong YP, Comiskey M, Kalled SL, et al. Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration. Gastroenterology. 2000;119:715–723.
Bauer P, Russell JM, Granger DN. Role of endotoxin in intestinal reperfusion-induced expression of E-selectin. Am J Physiol. 1999;276:G479–484.
Atkinson B, Dwyer K, Enjyoji K, Robson SC. Ecto-nucleotidases of the CD39/NTPDase family modulate platelet activation and thrombus formation: potential as therapeutic targets. Blood Cells Mol Dis. 2006;36(2):217–222.
Dranoff JA, Ogawa M, Kruglov EA, et al. Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G417–424.
Dwyer KM, Robson SC, Nandurkar HH, et al. Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation. J Clin Invest. 2004;113:1440–1446.
Friedman DJ, Kunzli BM YIAR, Sevigny J, et al. From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci USA. 2009;106:16788–16793.
Steinbrink K, Kolde G, Sorg C, Macher E. Induction of low zone tolerance to contact allergens in mice does not require functional Langerhans cells. J Invest Dermatol. 1996;107:243–247.
Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113:1490–1497.
Naganuma M, Wiznerowicz EB, Lappas CM, Linden J, Worthington MT, Ernst PB. Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol. 2006;177:2765–2769.
Kolachala VL, Vijay-Kumar M, Dalmasso G, et al. A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology. 2008;135:861–870.
Frick JS, MacManus CF, Scully M, Glover LE, Eltzschig HK, Colgan SP. Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis. J Immunol. 2009;182:4957–4964.
Acknowledgments
Supported by the German Research Foundation (DFG, KU-1957/3-1), the Lautenschläger Stipendium der Heidelberger Stiftung Chirurgie (to BMK) and the National Institutes of Health (NIH HL63972 and HL076540; to SCR).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Künzli, B.M., Berberat, P.O., Dwyer, K. et al. Variable Impact of CD39 in Experimental Murine Colitis. Dig Dis Sci 56, 1393–1403 (2011). https://doi.org/10.1007/s10620-010-1425-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-010-1425-9