title: Mitogen-activated protein kinase/IκB kinase/NF-κB-dependent and AP-1-independent CX3CL1 expression in intestinal epithelial cells stimulated with Clostridium difficile toxin A.
abstract: Clostridium difficile toxin A causes acute colitis associated with inflammatory cell infiltration and increased production of proinflammatory mediators. Although CX3CL1 (fractalkine) plays a role in chemoattracting monocytes/macrophages, NK cells, and T cells, little information is available on the regulated expression of CX3CL1 in response to toxin A stimulation. In this study, we investigated the role of C. difficile toxin A on CX3CL1 induction in intestinal epithelial cells. Stimulation of murine intestinal epithelial cells with toxin A resulted in the upregulation of CX3CL1. Expression of CX3CL1 was dependent on nuclear factor-kappaB (NF-κB) and IκB kinase (IKK) activation, while the suppression of activator protein-1 (AP-1) did not affect toxin A-induced CX3CL1 expression. Suppression of p38 mitogen-activated protein kinase (MAPK) significantly inhibited IKK-NF-κB signaling leading to CX3CL1 induction in C. difficile toxin A-stimulated cells. CX3CL1 was mainly secreted from the basolateral surfaces in toxin A-treated cells. Furthermore, inhibition of p38 activity attenuated the toxin A-induced upregulation of CX3CL1 in the mouse ileum in vivo. These results suggest that a pathway, including p38 MAPK, IKK, and NF-κB activation, is required for CX3CL1 induction in intestinal epithelial cells exposed to C. difficile toxin A and may regulate the development of intestinal inflammation induced by infection with toxigenic C. difficile.
  
  
  CONCLUSIONS
  C. difficile toxin A causes colitis with inflammatory cell infiltration. CX3CL1 plays a role in chemoattracting immune cells. MAPK-NF-κB signaling is required for CX3CL1 induction in toxin A-exposed cells. CX3CL1 is mainly secreted from the basolateral surfaces. CX3CL1 may contribute to the regulation of toxigenic C. difficile infection.
authors.affiliation: Department of Microbiology and Department of Biomedical Science, Hanyang University College of Medicine and Graduate School of Biomedical Science and Engineering, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-791, South Korea.
authors.forename: Su Hyuk
authors.initials: SH
authors.lastname: Ko
authors.forename: Jong Ik
authors.initials: JI
authors.lastname: Jeon
authors.forename: Hyunah
authors.initials: H
authors.lastname: Kim
authors.forename: Young-Jeon
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jeehee
authors.initials: J
authors.lastname: Youn
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003092:Colitis / Q000276:immunology / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D051550:I-kappa B Kinase / Q000378:metabolism; D007082:Ileum / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D061251:Primary Cell Culture; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D014709:Vero Cells
chemical_list: D001427:Bacterial Toxins; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D004768:Enterotoxins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C041348:tcdA protein, Clostridium difficile; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases