title: Clostridium difficile toxin A promotes dendritic cell maturation and chemokine CXCL2 expression through p38, IKK, and the NF-kappaB signaling pathway.
abstract: 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-kappaB) heterodimers and phospho-I kappa B kinase (IKK) in DCs. The increased DC maturation, CXCL2 expression, and neutrophil chemoattraction were significantly downregulated in the NF-kappaB 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-kappaB signaling, resulting in enhanced DC maturation and CXCL2 expression in response to C. difficile toxin A stimulation.
authors.affiliation: Department of Microbiology, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-791, South Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyunah
authors.initials: H
authors.lastname: Kim
authors.forename: Mi Yeon
authors.initials: MY
authors.lastname: Cha
authors.forename: Hong Gyu
authors.initials: HG
authors.lastname: Park
authors.forename: Young-Jeon
authors.initials: YJ
authors.lastname: Kim
authors.forename: In Young
authors.initials: IY
authors.lastname: Kim
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004768:Enterotoxins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D016130:Immunophenotyping; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D054426:Chemokine CXCL2; D004768:Enterotoxins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C041348:tcdA protein, Clostridium difficile; D008156:Luciferases; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases