Clostridium difficile toxin A promotes dendritic cell maturation and chemokine CXCL2 expression through p38, IKK, and the NF-κB signaling pathway
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Clostridium difficile toxin A causes acute colitis associated with intense infiltrating neutrophils. Although dendritic cells (DCs) play an important role in the regulation of inflammation, little is known about the effects of toxin A on the maturation and neutrophil-attracting chemokine expression in DCs. This study investigated whether C. difficile toxin A could influence the maturation of mouse bone-marrow-derived DCs and chemokine CXCL2 expression. Toxin A increased the DC maturation which was closely related to CXCL2 upregulation. Concurrently, toxin A activated the signals of p65/p50 nuclear factor kappa B (NF-κB) heterodimers and phospho-IκB kinase (IKK) in DCs. The increased DC maturation, CXCL2 expression, and neutrophil chemoattraction were significantly downregulated in the NF-κB knockout mice. In addition, toxin A activated the phosphorylated signals of mitogen-activated protein kinases (MAPKs), such as ERK, p38, and JNK. Of all three MAPK signals, p38 MAPK was significantly related to DC maturation. Thus, suppression of p38 activity using SB203580 and siRNA transfection resulted in the significant reduction of IKK activity, DC maturation, and CXCL2 upregulation by toxin A. These results suggest that p38 MAPK may lead to the activation of IKK and NF-κB signaling, resulting in enhanced DC maturation and CXCL2 expression in response to C. difficile toxin A stimulation.
KeywordsClostridium difficile toxin A Dendritic cells Maturation CXCL2 Mitogen-activated protein kinase
We thank Dr. Martin F. Kagnoff for providing plasmids of murine β-actin internal standard, Dr. Hyung-Joo Kwon for the pMIP-2-luciferease plasmid, Dr. Kyoung-Ho Kim for performing the animal studies, and Han-Jin Lee for the excellent technical assistance. This work was supported by MRC Program from the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MEST; R13-2008-026-01000-0).
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