Pediatric Surgery International

, Volume 22, Issue 1, pp 84–89 | Cite as

Gene expression profile of the infective murine model for biliary atresia

  • Johannes Leonhardt
  • Martin Stanulla
  • Reinhard von Wasielewski
  • Julia Skokowa
  • Joachim Kübler
  • Benno M. Ure
  • Claus Petersen
Original Article


One hypothesis of the pathogenesis of biliary atresia (BA) is a virus-induced and immune-mediated injury to bile duct cells as mimicked in the rotavirus-induced murine model. This theory is supported by studies showing a predominant T helper cell response type 1-like phenotype of inflammation with increased interferon gamma-induced chemokines in the liver of humans and mice suffering from BA. Recent gene expression profiling studies using microarray analysis showed the induction of a proinflammatory state in human liver specimens with high analogies in extrahepatic biliary tissue of BA mice. The aim of the present study was a microarray analysis of gene expression in the liver of Balb/c mice, comparing infected mice that show the phenotype of BA versus infected mice without symptoms, thus trying to elucidate genes that are not related to the viral origin of this model, but to the specific pathogenesis of the clinical picture of BA. Fifteen μg of RNA, each of three BA-positive and three BA-negative mice, were pooled and comparatively hybridized to spotted cDNA microarrays containing 250 key genes with high relevance to immunological settings. We identified the 40 genes most differentially expressed in mice with and without BA. The majority of genes with higher expression in BA-positive mice encoded proinflammatory cytokines involved in the Th1 pathway, such as CCL2, CCL5, CCR5, CXCL10, CCL2, IL1F5 and in apoptosis, such as DDR3 and granzyme A and B. In this initial study of the molecular characterization of our RRV-induced BA mouse model system, we also found potential novel candidates important to BA etiology, such as growth hormone receptor and insulin-like growth factor. Of particular interest, very low expression of TIMD2 was observed in BA-positive mice. TIMD2 plays a critical role in the regulation of a Th2-type response through the inhibition of IFN gamma.


Bile Duct Biliary Atresia Extrahepatic Bile Duct Growth Hormone Receptor Specific Pathogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank Ms Birgit Teichmann for technical assistance and Ms Clare Boerner for revising the text. This work was supported by a grant (HiLFI) from the Hannover Medical School, Germany.


  1. 1.
    Petersen C (2005) Pathogenesis and treatment opportunities for biliary atresia. Clin Liver Dis (in press)Google Scholar
  2. 2.
    Schreiber RA, Kleinman RE (2002) Biliary atresia. J Pediatr Gastroenterol Nutr 35:11–16CrossRefGoogle Scholar
  3. 3.
    Mack CL, Tucker RM, Sokol RJ, Karrer FM, Kotzin BL, Whitington PF, Miller SD.(2004) Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation. Pediatr Res. 56:79–87CrossRefPubMedGoogle Scholar
  4. 4.
    Riepenhoff-Talty M, Schaekel K, Clark H, Mueller W, Uhnoo I, Rossi T, Fisher J, Ogra PL (1993) Group A rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res 33:394–399PubMedCrossRefGoogle Scholar
  5. 5.
    Petersen C, Biermanns D, Kuske M, Schakel K, Meyer-Junghanel L, Mildenberger H (1997) New aspects in a murine model for extrahepatic biliary atresia. J Pediatr Surg 32:1190–1195CrossRefPubMedGoogle Scholar
  6. 6.
    Czech-Schmidt G, Verhagen W, Szavay P, Leonhardt J, Petersen C (2001) Immunological gap in the infectious animal model for biliary atresia. J Surg Res 101:62–67CrossRefPubMedGoogle Scholar
  7. 7.
    Chan R, Tan CL, Czech-Schmidt G, Petersen C (2005) Computerized three-dimensional study of a rotavirus model of biliary atresia: comparison with human biliary atresia. Pediatr Surg Int 21:615–620CrossRefPubMedGoogle Scholar
  8. 8.
    Shivakumar P, Campbell KM, Sabla GE, Miethke A, Tiao G, McNeal MM, Ward RL, Bezerra JA (2004) Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest 114(3):322–329CrossRefPubMedGoogle Scholar
  9. 9.
    Bezerra JA, Tiao G, Ryckman FC, Alonso M, Sabla GE, Shneider B, Sokol RJ, Aronow BJ (2002) Genetic induction of proinflammatory immunity in children with biliary atresia. Lancet 360:1653–1659CrossRefPubMedGoogle Scholar
  10. 10.
    Carvalho E, Liu C, Shivakumar P, Sabla G, Aronow B, Bezerra J (2005) Analysis of the biliary transcriptome in experimental biliary atresia. Gastroenterol 129:713–17CrossRefGoogle Scholar
  11. 11.
    Bosio A, Knorr C, Janssen U, Gebel S, Haussmann HJ, Muller T (2002) Kinetics of gene expression profiling in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke. Carcinogenesis 23:741–748CrossRefPubMedGoogle Scholar
  12. 12.
    Cario G, Stanulla M, Fine BM, Teuffel O, Neuhoff NV, Schrauder A, Flohr T, Schafer BW, Bartram CR, Welte K, Schlegelberger B, Schrappe M. (2005). Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia. Blood 105:821–826CrossRefPubMedGoogle Scholar
  13. 13.
    Petersen C, Grasshoff S, Luciano L (1998) Diverse morphology of biliary atresia in an animal model. J Hepatol. 28:603–607CrossRefPubMedGoogle Scholar
  14. 14.
    Mack CL, Tucker RM, Sokol RJ, Kotzin BL (2005) Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia. Clin Immunol. 115(2):200–209CrossRefPubMedGoogle Scholar
  15. 15.
    Carroll M (2004) The complement system in regulation of adaptive immunity. Nature Immunology 5:981–986CrossRefPubMedGoogle Scholar
  16. 16.
    Ajuebor MN, Hogaboam CM, Proudfoot AI, Swain MG (2004) CCL3/MIP-1α is proinflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4+ T cells to the liver. Eur J Immunol 34:2907–2918CrossRefPubMedGoogle Scholar
  17. 17.
    Chakravarti S, Sabatos CA, Xiao S, Illes Z, Cha EK, Sobel RA, Zheng X, Strom T, Kuchroo V (2005) Tim-2 regulates T helper type 2 responses and autoimmunity. J Ex Med 202:437–444CrossRefGoogle Scholar
  18. 18.
    Koniaris LG, Zimmers-Koniaris T, Hsiao EC, Chavin K, Sitzmann JV, Farber JM (2001) Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiple models of liver and bile duct injury suggests a role in tissue regeneration. J Immunol 167:399–406PubMedGoogle Scholar
  19. 19.
    Yoshida S, Nio M, Hayashi Y, Ohi R, Kawamura I, Goto T (2003) Serum insulinlike growth factor-1 in biliary atresia. J Ped Surg 38: 211–215CrossRefGoogle Scholar
  20. 20.
    Held MA, Cosme-Blanco W, Difedele LM, Bonkowski EL, Menon RK, Denson LA (2004) Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis. Am J Physiol Gastrointest Liver Physiol 288:986–993CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Johannes Leonhardt
    • 1
  • Martin Stanulla
    • 2
  • Reinhard von Wasielewski
    • 3
  • Julia Skokowa
    • 2
  • Joachim Kübler
    • 1
  • Benno M. Ure
    • 1
  • Claus Petersen
    • 1
  1. 1.Department of Pediatric SurgeryHannover Medical SchoolHannoverGermany
  2. 2.Department of Pediatric Hematology and Oncology Hannover Medical SchoolHannoverGermany
  3. 3.Department of PathologyHannover Medical SchoolHannoverGermany

Personalised recommendations