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RECEPTORS AND SIGNAL TRANSDUCTION

Monochloramine induces reorganization of nuclear speckles and phosphorylation of SRp30 in human colonic epithelial cells: role of protein kinase C

¹Disease Pathogenesis Program, Children's Memorial Institute for Education and Research, Chicago; and ²Department of Pathology, Children's Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614

Submitted 5 March 2003 ; accepted in final form 19 June 2003

Intestinal epithelial cells are constantly stimulated by reactive oxidant metabolites (ROMs) in inflamed mucosa. Monochloramine (NH₂Cl), a cell-permeant ROM, is particularly relevant to the pathogenesis of inflammation in the gastrointestinal tract. Nuclear speckles, a unique nuclear subcompartment, accumulate a family of proteins, namely, serine- and arginine-rich (SR) proteins. They play important roles in regulation of pre-mRNA splicing. Currently, little is known about the link between inflammatory stimulation and the pre-mRNA splicing process, although gene expression is changed in inflamed tissues. The present study was designed to investigate whether stimulation of human colonic epithelial cells (HT-29 and Caco-2 cell lines) with NH₂Cl affects nuclear speckles and their components. By indirect immunofluorescence, nuclear speckles have been shown to undergo rapid aggregation after NH₂Cl stimulation. By utilizing Western blotting, SRp30 (a subset of SR proteins) in intestinal epithelial cells was found to be phosphorylated after NH₂Cl treatment, whereas other SR proteins were not responsive to NH₂Cl stimulation. The cytotoxic effect of NH₂Cl was excluded by both negative lactate dehydrogenase assay and propidium iodide staining. Therefore, NH₂Cl-induced morphological changes on nuclear speckles and phosphorylated SRp30 do not result from intestinal epithelial injury. Furthermore, the effect of NH₂Cl on nuclear speckles and SRp30 was blocked by bisindolylmaleimide I, a selective PKC inhibitor. Together, the available data suggest that stimulation of intestinal epithelial cells with NH₂Cl results in a consequent change on pre-mRNA splicing machinery via a distinctive signal pathway involving activation of PKC. This effect may contribute to oxidant-induced pathophysiological changes in the gastrointestinal tract.

intestinal epithelial cell; reactive oxygen metabolites; premRNA splicing machinery; SR proteins; signal transduction

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