Digestive Diseases and Sciences

, Volume 54, Issue 3, pp 547–554 | Cite as

Activation of Interleukin-6/STAT3 in Rat Cholangiocyte Proliferation Induced by Lipopolysaccharide

  • Li-Ping Chen
  • Ming Cai
  • Qi-Hao Zhang
  • Zhou-Li Li
  • Ye-Yong Qian
  • Hong-Wei Bai
  • Xing Wei
  • Bing-Yi Shi
  • Jia-Hong Dong
Original Article


Background Cholangiocytes are exposed to endotoxins (lipopolysaccharide, LPS) in a variety of biliary inflammations. It is known that LPS enhances the release of interleukin (IL)-6, a potent cholangioycte mitogen. However, the role of LPS in cholangiocyte proliferation in vivo is unknown. Aims To investigate whether LPS stimulates cholangiocyte proliferation in vivo via the IL-6/STAT3 pathway. Methods Rats were randomized into four groups: the LPS group (injected intravenously with LPS 2.5 mg/kg), anti-IL-6 group (injected intravenously with anti-IL-6 0.5 mg/kg 1 h after LPS injection), RPM group (treated with RPM 0.4 mg/kg intraperitoneally 30 min before LPS injection), and control group. At 6, 12, 24, 48, and 72 h after LPS injection, LPS in plasma was detected by kinetic turbidimetric limulus test. IL-6 concentrations in liver homogenate and cholangiocyte proliferation were determined by ELISA or immunohistochemistry, respectively. Expression of IL-6 mRNA and phophorylated-STAT3 (P-STAT3) protein in cholangiocytes was analyzed by real-time RT-PCR and western blotting. Results Cholangiocytes responded to LPS by a marked increase in cell proliferation, IL-6 secretion, and P-STAT3 expression. Anti-IL-6 neutralizing antibody inhibited LPS-induced proliferation of cholangiocytes and decreased levels of IL-6 and STAT3. Furthermore, after being treated with RPM, STAT3 activation was also depressed, which resulted a decreased proliferation of cholangiocytes. Conclusions LPS promotes cholangiocyte proliferation through the IL-6/STAT3 pathway, while RPM shows a depressive effect in this pathway.


Lipopolysaccharide Cholangiocyte Interleukin-6 Signal transducers and activation of transcription 3 Proliferation 


  1. 1.
    Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M et al (2006) Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 12(22):3523–3536PubMedGoogle Scholar
  2. 2.
    Ramadori G, Saile B (2004) Portal tract fibrogenesis in the liver. Lab Invest 84(2):153–159. doi:10.1038/labinvest.3700030 PubMedCrossRefGoogle Scholar
  3. 3.
    Netea MG, van der Graaf C, Van der Meer JW, Kullberg BJ (2003) Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. J Leukoc Biol 75(5):749–755. doi:10.1189/jlb.1103543 CrossRefGoogle Scholar
  4. 4.
    Nozaki I, Lunz JG 3rd, Specht S, Park JI, Giraud AS, Murase N et al (2004) Regulation and function of trefoil factor family 3 expression in the biliary tree. Am J Pathol 165(6):1907–1920PubMedGoogle Scholar
  5. 5.
    Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE et al (2005) Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 65(3):939–47PubMedGoogle Scholar
  6. 6.
    Park J, Gores GJ, Patel T (1999) Lipopolysaccharide induces cholangiocyte proliferation via an interleukin-6-mediated activation of p44/p42 mitogen-activated protein kinase. Hepatology 29(4):1037–1043. doi:10.1002/hep. 510290423 PubMedCrossRefGoogle Scholar
  7. 7.
    Forgacs B, Merhav HJ, Lappin J, Mieles L (2005) Successful conversion to rapamycin for calcineurin inhibitor-related neurotoxicity following liver transplantation. Transplant Proc 37(4):1912–1914. doi:10.1016/j.transproceed.2005.02.101 PubMedCrossRefGoogle Scholar
  8. 8.
    Aznar S, Valerón PF, del Rincon SV, Pérez LF, Perona R, Lacal JC (2001) Simultaneous tyrosine and serine phosphorylation of Stat3 transcription factor is involved in Rho A GTPase oncogenic transformation. Mol Biol Cell 12(10):3282–3294PubMedGoogle Scholar
  9. 9.
    Hagiwara S, Iwasaka H, Shingu C, Noguchi T (2008) Effect of enteral versus parenteral nutrition on LPS-induced sepsis in a rat model. J Surg Res 145(2):251–256. doi:10.1016/j.jss.2007.06.012 PubMedCrossRefGoogle Scholar
  10. 10.
    Pallua N, Low JF, von Heimburg D (2003) Pathogenic role of interleukin-6 in the development of sepsis. Part II: Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-alpha antibodies in a standardized murine contact burn model. Crit Care Med 31(5):1495–1501. doi:10.1097/01.CCM.0000065725.80882.BD PubMedCrossRefGoogle Scholar
  11. 11.
    Liu H, Yao YM, Yu Y, Dong N, Yin HN, Sheng ZY (2007) Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock 27(1):55–60. doi:10.1097/01.shk.0000233197.40989.31 PubMedCrossRefGoogle Scholar
  12. 12.
    Gigliozzi A, Alpini G, Baroni GS, Marucci L, Metalli VD, Glaser SS et al (2004) Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis. Gastroenterology 127(4):1198–1209. doi:10.1053/j.gastro.2004.06.023 PubMedCrossRefGoogle Scholar
  13. 13.
    Rutenburg AM, Kim H, Fischbein JW, Hanker JS, Wasserkrug HL, Seligman AM (1969) Histochemical and ultrastructural demonstration of gamma-glutamyl transpeptidase activity. J Histochem Cytochem 17(8):517–526PubMedGoogle Scholar
  14. 14.
    Teutsch HF (1978) Improved method for the histochemical demonstration of glucose-6-phosphatase activity. A methodological study. Histochemistry 57:107–117. doi:10.1007/BF00496675 PubMedCrossRefGoogle Scholar
  15. 15.
    Hsieh FC, Cheng G, Lin J (2005) Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 335(2):292–299. doi:10.1016/j.bbrc.2005.07.075 PubMedCrossRefGoogle Scholar
  16. 16.
    Lamireau T, Zoltowska M, Levy E, Yousef I, Rosenbaum J, Tuchweber B et al (2003) Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity, and cytokine secretion. Life Sci 72(12):1401–1411. doi:10.1016/S0024-3205(02)02408-6 PubMedCrossRefGoogle Scholar
  17. 17.
    Demetris AJ, Lunz JG 3rd, Specht S, Nozaki I (2006) Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol 12(22):3512–3522PubMedGoogle Scholar
  18. 18.
    Yokomuro S, Lunz JG 3rd, Sakamoto T, Ezure T, Murase N, Demetris AJ (2000) The effect of interleukin-6 (IL-6)/gp130 signaling on biliary epithelial cell growth, in vitro. Cytokine 12(6):727–730. doi:10.1006/cyto.1999.0612 PubMedCrossRefGoogle Scholar
  19. 19.
    Liu Z, Sakamoto T, Yokomuro S, Ezure T, Subbotin V, Murase N et al (2000) Acute obstructive cholangiopathy in interleukin-6 deficient mice: compensation by leukemia inhibitory factor (LIF) suggests importance of gp-130 signaling in the ductular reaction. Liver 20(2):114–124. doi:10.1034/j.1600-0676.2000.020002114.x PubMedCrossRefGoogle Scholar
  20. 20.
    Kimmings AN, van Deventer SJ, Rauws EAJ, Huibregtse K, Gouma DJ (2000) Systemic inflammatory response in acute cholangitis and after subsequent treatment. Eur J Surg 166(9):700–705. doi:10.1080/110241500750008457 PubMedCrossRefGoogle Scholar
  21. 21.
    Kimmings AN, van Deventer SJ, Obertop H, Rauws EA, Huibregtse K, Gouma DJ (2000) Endotoxin, cytokines, and endotoxin binding proteins in obstructive jaundice and after preoperative biliary drainage. Gut 46(5):725–731. doi:10.1136/gut.46.5.725 PubMedCrossRefGoogle Scholar
  22. 22.
    Strazzabosco M, Fabris L, Spirli C (2005) Pathophysiology of cholangiopathies. J Clin Gastroenterol 39 Suppl 2(4):S90–102. doi:10.1097/01.mcg.0000155549.29643.ad Google Scholar
  23. 23.
    Lehle K, Birnbaum DE, Preuner JG (2005) Predominant inhibition of interleukin-6 synthesis in patient-specific endothelial cells by mTOR inhibitors below a concentration range where cell proliferation is affected and mitotic arrest takes place. Transplant Proc 37(1):159–161. doi:10.1016/j.transproceed.2004.12.140 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Li-Ping Chen
    • 1
  • Ming Cai
    • 1
  • Qi-Hao Zhang
    • 2
  • Zhou-Li Li
    • 1
  • Ye-Yong Qian
    • 1
  • Hong-Wei Bai
    • 1
  • Xing Wei
    • 1
  • Bing-Yi Shi
    • 1
  • Jia-Hong Dong
    • 3
  1. 1.Organ Transplantation CenterSecond Hospital Affiliated to General Hospital of PLABeijingChina
  2. 2.Institutes of Life and Health EngineeringJinan UniversityGuangzhouChina
  3. 3.Hepatobiliary Surgery Department of General Hospital of PLABeijingChina

Personalised recommendations