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(American Journal of Pathology. 2002;161:987-996.)
© 2002 American Society for Investigative Pathology


Regular Articles

Hyperosmotic Stress Induces Nuclear Factor-{kappa}B Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells

Zoltán H. Németh, Edwin A. Deitch, Csaba Szabó and György Haskó

From the Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey

Inflammatory bowel disease of the colon is associated with a high osmolarity of colonic contents. We hypothesized that this hyperosmolarity may contribute to colonic inflammation by stimulating the proinflammatory activity of intestinal epithelial cells (IECs). The human IEC lines HT-29 and Caco-2 were used to study the effect of hyperosmolarity on the IEC inflammatory response. Exposure of IECs to hyperosmolarity triggered expression of the proinflammatory chemokine interleukin (IL)-8 both at the secreted protein and mRNA levels. In addition, hyperosmotic stimulation induced the release of another chemokine, GRO-{alpha}. These effects were because of activation of the transcription factor, nuclear factor (NF)-{kappa}B, because hyperosmolarity stimulated both NF-{kappa}B DNA binding and NF-{kappa}B-dependent transcriptional activity. Hyperosmolarity activated both p38 and p42/44 mitogen-activated protein kinases, which effect contributed to hyperosmolarity-stimulated IL-8 production, because p38 and p42/44 inhibition prevented the hyperosmolarity-induced increase in IL-8 production. In addition, the proinflammatory effects of hyperosmolarity were, in a large part, mediated by activation of Na+/H+ exchangers, because selective blockade of Na+/H+ exchangers prevented the hyperosmolarity-induced IEC inflammatory response. In summary, hyperosmolarity stimulates IEC IL-8 production, which effect may contribute to the maintenance of inflammation in inflammatory bowel disease.





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