Gene regulation and expression of chemokines in response to bacterial enterotoxins

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Bacterial enterotoxins are proteins released by specific bacterial organisms in the intestine and are chromosomally encoded exotoxins. The first host cells that enterotoxins interact with are intestinal epithelial cells, after which mucosal inflammatory signals are initiated. Characteristic features of inflammatory signals are the chemokine expression, leading to the migration of inflammatory cells into intestinal mucosa. Several microbial organisms produce the enterotoxin to create such an effect. These bacteria contain enterotoxigenic Bacteroides fragilis, Clostridium difficile and Staphylococcus aureus. This chapter will focus on the impact of bacterial enterotoxins on the gene regulation and expression of chemokines in intestinal epithelial cells. Enterotoxins produced from those bacteria up-regulate the expression of CXC and CC chemokines. The kinetics of each chemokine expression is different. For example, expression of the CXC chemokines, including IL-8 and growth-related oncogene (GRO)-α, and the CC chemokines, including monocyte chemoattractant protein (MCP)-1, increases during the relatively early period after stimulation with C. difficile enterotoxin (toxin A) and B. fragilis enterotoxin. In contrast, expression of neutrophil activating protein-78 (ENA-78) is delayed. These findings suggest that the chemokines can contribute to the infiltration of inflammatory cells in the underlying infected intestinal mucosa. Bacterial enterotoxins can induce the NF-κB signals. Major subunits of the activated NF-κB complexes are p65/p50 heterodimers and p65/p65 homodimers. The IκB kinase (IKK) complexes induced by enteroroxins contain three subunits: two catalytic subunits, IKK-α and IKK-β, and a regulatory subunit, IKK-Υ{hooked (also known as NEMO, NF-κB essential modulator). siRNA for IKK-β dramatically reduces B. fragilis enterortoxin-induced IαBκ phosphorylation compared with IKK-α. In addition, IKK-α and -Υ{hooked interact strongly with heat shock protein 90 (Hsp90) in B. fragilis enterotoxin-stimulated intestinal epithelial cells, suggesting that activating Hsp90 and IKK complex is involved in the gene regulation of chemokines in response to enterotoxin stimulation. In addition, enterotoxins can activate mitogen-activated protein kinase (MAPK) and AP-1 composed of c-Jun/c-Fos heterodimers in intestinal epithelial cells. Transfection with adenovirus containing dominant-negative p38 or c-Jun N-terminal kinase (JNK) expression vectors significantly inhibits IL-8 expression in enterotoxin-stimulated cells. Concurrently, MAPK may regulate IKK activation in intestinal epithelial cells. Furthermore, the secretion of macrophage-inflammatory protein (MIP)-2, a murine homologue of IL-8, and the increased IKK activity induced by enterotoxins are significantly reduced when p38 MAPK activity is suppressed in an in vivo murine model. Based on these findings, the exposure of intestinal epithelial cells to enterotoxins may result in the rapid activation of MAPK signaling pathways, leading to NF-κB/AP-1 activation and chemokine gene expression. Notably, chemokines are predominantly secreted from the basolateral surface of epithelial cells stimulated with enterotoxins. Specific targeting of these signaling pathways may therefore be effective in the prevention or treatment of inflammation associated with infection by toxin-producing bacteria.

Original languageEnglish
Title of host publicationChemokines
Subtitle of host publicationTypes, Functions, and Structural Characteristics
PublisherNova Science Publishers, Inc.
Number of pages22
ISBN (Print)9781617288616
StatePublished - 2011 Jan 1

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    Kim, J. M. (2011). Gene regulation and expression of chemokines in response to bacterial enterotoxins. In Chemokines: Types, Functions, and Structural Characteristics (pp. 89-110). Nova Science Publishers, Inc..