Journal of Microbiology and Biotechnology
The Korean Society for Microbiology and Biotechnology publishes the Journal of Microbiology and Biotechnology.
Journal of Microbiology and Biotechnology
Condition  Expression
When you enter More than two words, please use ‘and , or’ operation by means of putting ‘,(Comma Mark)’ between each word.

2012 ; 22(12): 1629~1635

AuthorSeung Taek Nam, Heon Seok, Dae Hong Kim, Hyo Jung Nam, Jin Ku Kang, Jang Hyun Eom, Min Bum Lee, Sung Kuk Kim, Mi Jung Park, Jong Soo Chang, Eun-Mi Ha, Ko Eun Shong, Jae Sam Hwang, Ho Kim
AffiliationDepartment of Life Science, College of Natural Science, Daejin University, Pocheon 487-711, Korea
TitleClostridium difficile Toxin A Inhibits Erythropoietin Receptor-Mediated Colonocyte Focal Adhesion Through Inactivation of Janus Kinase-2
PublicationInfo J. Microbiol. Biotechnol.2012 ; 22(12): 1629~1635
AbstractPreviously, we demonstrated that the erythropoietin receptor (EpoR) is present on fibroblasts, where it regulates focal contact. Here, we assessed whether this action of EpoR is involved in the reduced cell adhesion observed in colonocytes exposed to Clostridium difficile toxin A. EpoR was present and functionally active in cells of the human colonic epithelial cell line HT29 and epithelial cells of human colon tissues. Toxin A significantly decreased activating phosphorylations of EpoR and its downstream signaling molecules JAK-2 (Janus kinase 2) and STAT5 (signal transducer and activator of transcription 5). In vitro kinase assays confirmed that toxin A inhibited JAK 2 kinase activity. Pharmacological inhibition of JAK2 (with AG490) abrogated activating phosphorylations of EpoR and also decreased focal contacts in association with inactivation of paxillin, an essential focal adhesion molecule. In addition, AG490 treatment significantly decreased expression of occludin (a tight junction molecule) and tight junction levels. Taken together, these data suggest that inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR, thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A.
Full-Text(PDF)
Keywordsclostridium difficile, toxin, gut inflammation, epithelial cell adhesion, erythropoietin receptor, JAK/STAT pathways
References
  1. Alscher, K. T., P. T. Phang, T. E. McDonald, and K. R. Walley. 2001. Enteral feeding decreases gut apoptosis, permeability, and lung inflammation during murine endotoxemia. Am. J. Physiol. Gastrointest. Liver Physiol. 281: G569-G576.
    Pubmed
  2. Chang, J. S., D. Y. Noh, I. A. Park, M. J. Kim, H. Song, S. H. Ryu, and P. G. Suh. 1997. Overexpression of phospholipase Cgamma1 in rat 3Y1 fibroblast cells leads to malignant transformation. Cancer Res. 57: 5465-5468.
    Pubmed
  3. Choi, H. R., W. K. Kim, E. Y. Kim, H. Jung, J. H. Kim, B. S. Han, et al. 2012. Protein tyrosine phosphatase profiling analysis of HIB-1B cells during brown adipogenesis. J. Microbiol. Biotechnol. 22: 1029-1033.
    Pubmed CrossRef
  4. Di Bona, D., M. Cippitelli, C. Fionda, C. Camma, A. Licata, A. Santoni, and A. Craxi. 2006. Oxidative stress inhibits IFNalphainduced antiviral gene expression by blocking the JAKSTAT pathway. J. Hepatol. 45: 271-279.
    Pubmed CrossRef
  5. Farrell, F. and A. Lee. 2004. The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist 5:18-30.
    Pubmed CrossRef
  6. Huang, L. J., S. N. Constantinescu, and H. F. Lodish. 2001. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol. Cell 8: 1327-1338.
    CrossRef
  7. Jang, E. H., C. S. Park, S. K. Lee, J. E. Pie, and J. H. Kang. 2007. Excessive nitric oxide attenuates leptin-mediated signal transducer and activator of transcription 3 activation. Life Sci. 80: 609-617.
    Pubmed CrossRef
  8. Just, I., G. Fritz, K. Aktories, M. Giry, M. R. Popoff, P. Boquet, et al. 1994. Clostridium difficile toxin B acts on the GTPbinding protein Rho. J. Biol. Chem. 269: 10706-10712.
    Pubmed
  9. Just, I., J. Selzer, C. von Eichel-Streiber, and K. Aktories. 1995. The low molecular mass GTP-binding protein Rho is affected by toxin A from Clostridium difficile. J. Clin. Invest. 95: 10261031.
    Pubmed CrossRef Pubmed Central
  10. Just, I., J. Selzer, M. Wilm, C. von Eichel-Streiber, M. Mann, and K. Aktories. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375: 500-503.
    Pubmed CrossRef
  11. Just, I., M. Wilm, J. Selzer, G. Rex, C. von Eichel-Streiber, M. Mann, and K. Aktories. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270: 13932-13936.
  12. Kang, J. K., C. H. Chang, H. J. Nam, S. K. Kim, K. J. Ahn, H. Seok, et al. 2010. Downregulation of erythropoietin receptor by overexpression of phospholipase C-gamma 1 is critical for decrease on focal adhesion in transformed cells. Cell Oncol. (Dordr) 34: 11-21.
  13. Kim, H., E. Kokkotou, X. Na, S. H. Rhee, M. P. Moyer, C. Pothoulakis, and J. T. Lamont. 2005. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129: 1875-1888.
    Pubmed CrossRef
  14. Kim, H., S. H. Rhee, E. Kokkotou, X. Na, T. Savidge, M. P. Moyer, et al. 2005. Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 MAPK. J. Biol. Chem. 280: 21237-21245.
    Pubmed CrossRef
  15. Kim, H., S. H. Rhee, C. Pothoulakis, and J. T. LaMont. 2009. Clostridium difficile toxin A binds colonocyte Src causing dephosphorylation of focal adhesion kinase and paxillin. Exp. Cell Res. 315: 3336-3344.
    Pubmed CrossRef Pubmed Central
  16. Kim, H., S. H. Rhee, C. Pothoulakis, and J. T. Lamont. 2007. Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand. Gastroenterology 133: 875-886.
    Pubmed CrossRef
  17. Kurdi, M. and G. W. Booz. 2007. Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling. J. Cardiovasc. Pharmacol. 50: 126-141.
    Pubmed CrossRef
  18. Lacombe, C. and P. Mayeux. 1999. Erythropoietin (Epo) receptor and Epo mimetics. Adv. Nephrol. Necker Hosp. 29:177-189.
    Pubmed
  19. Lamont, J. T. 2002. Theodore E. Woodward Award. How bacterial enterotoxins work: Insights from in vivo studies. Trans. Am. Clin. Climatol. Assoc. 113: 167-180; discussion 180-181.
    Pubmed Pubmed Central
  20. Mazzoni, A., V. Bronte, A. Visintin, J. H. Spitzer, E. Apolloni, P. Serafini, et al. 2002. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168:689-695.
    Pubmed
  21. Menier, C., C. Guillard, B. Cassinat, E. D. Carosella, and N. Rouas-Freiss. 2008. HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation:Clinical relevance in polycythemia vera. Leukemia 22: 578-584.
    Pubmed CrossRef
  22. Nam, H. J., J. K. Kang, S. K. Kim, K. J. Ahn, H. Seok, S. J. Park, et al. 2011. Clostridium difficile toxin A decreases acetylation of tubulin, leading to microtubule depolymerization through activation of histone deacetylase 6, and this mediates acute inflammation. J. Biol. Chem. 285: 32888-32896.
    Pubmed CrossRef Pubmed Central
  23. Neumann, D., L. Wikstrom, S. S. Watowich, and H. F. Lodish. 1993. Intermediates in degradation of the erythropoietin receptor accumulate and are degraded in lysosomes. J. Biol. Chem. 268:13639-13649.
    Pubmed
  24. Pothoulakis, C., R. J. Gilbert, C. Cladaras, I. Castagliuolo, G. Semenza, Y. Hitti, et al. 1996. Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J. Clin. Invest. 98: 641-649.
    Pubmed CrossRef Pubmed Central
  25. Pothoulakis, C. and J. T. Lamont. 2001. Microbes and microbial toxins: Paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am. J. Physiol. Gastrointest. Liver Physiol. 280: G178G183.
  26. Pothoulakis, C., R. Sullivan, D. A. Melnick, G. Triadafilopoulos, A. S. Gadenne, T. Meshulam, and J. T. LaMont. 1988. Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes. J. Clin. Invest. 81: 1741-1745.
    Pubmed CrossRef Pubmed Central
  27. Teter, K., M. G. Jobling, D. Sentz, and R. K. Holmes. 2006. The cholera toxin A1(3) subdomain is essential for interaction with ADP-ribosylation factor 6 and full toxic activity but is not required for translocation from the endoplasmic reticulum to the cytosol. Infect. Immun. 74: 2259-2267.
    Pubmed CrossRef Pubmed Central
  28. Walrafen, P., F. Verdier, Z. Kadri, S. Chretien, C. Lacombe, and P. Mayeux. 2005. Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood 105: 600-608.
    Pubmed CrossRef
  29. Warny, M., A. C. Keates, S. Keates, I. Castagliuolo, J. K. Zacks, S. Aboudola, et al. 2000. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J. Clin. Invest. 105: 1147-1156.
    Pubmed CrossRef Pubmed Central
  30. Xiong, H., Z. G. Zhang, X. Q. Tian, D. F. Sun, Q. C. Liang, Y. J. Zhang, et al. 2008. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 10: 287-297.
    Pubmed Pubmed Central
  31. Yoshimura, A., A. D. D’Andrea, and H. F. Lodish. 1990. Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc. Natl. Acad. Sci. USA 87: 41394143.
    CrossRef
Copyright © 2009 by the Korean Society for Microbiology and Biotechnology.
All right reserved. Mail to jmb@jmb.or.kr
Online ISSN: 1738-8872    Print ISSN: 1017-7825    Powered by INFOrang Co., Ltd