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

UNLABELLED:

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.

KEY MESSAGE:

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: Su Hyuk Ko, Jong Ik Jeon, Hyunah Kim, Young-Jeon Kim, Jeehee Youn, Jung Mogg Kim
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 92 Issue 4 Pg. 411-27 (Apr 2014) ISSN: 1432-1440 [Electronic] Germany
• PMID: 24362517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Chemokine CX3CL1
• Cx3cl1 protein, mouse
• Enterotoxins
• NF-kappa B
• Transcription Factor AP-1
• tcdA protein, Clostridium difficile
• I-kappa B Kinase
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Bacterial Toxins (pharmacology)
• Chemokine CX3CL1 (genetics, metabolism)
• Chlorocebus aethiops
• Colitis (immunology, metabolism)
• Enterotoxins (pharmacology)
• Enzyme Activation
• Epithelial Cells (immunology, metabolism)
• Gene Expression
• I-kappa B Kinase (metabolism)
• Ileum (immunology, metabolism, pathology)
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Primary Cell Culture
• Transcription Factor AP-1 (metabolism)
• Transcriptional Activation (immunology)
• Up-Regulation (immunology)
• Vero Cells