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Differential Pattern of Inflammatory Molecule Regulation in Intestinal Epithelial Cells Stimulated with IL-1¹

Sen Rong Yan^2,*, Robbie R. Joseph, Jun Wang^*, and Andrew W. Stadnyk^3,*,

^* Department of Pediatrics, Department of Microbiology and Immunology, and the Dalhousie Inflammation Group, Dalhousie University, Halifax, Nova Scotia, Canada

To better predict the consequences of blocking signal transduction pathways as a means of controlling intestinal inflammation, we are characterizing the pathways up-regulated by IL-1 in intestinal epithelial cells (IEC). IL-1 induced increased mRNA levels of MIP-2, MCP-1, RANTES, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) in the IEC-18 cell line. IL-1 activated NF-B but not ERK or p38. Infecting cells with adenovirus expressing a mutated gene for IB (IBAA) blocked IL-1-induced mRNA increases in MIP-2, MCP-1, and iNOS but not COX-2 or RANTES. Expression of IBAA attenuated the IL-1-induced increase in COX-2 protein. Unexpectedly, RANTES mRNA increased, and protein was secreted by cells expressing IBAA in the absence of IL-1. Adenovirus-expressing IBAA, blocking protein synthesis, and IL-1 all resulted in activation of JNK. The JNK inhibitor SP600125 prevented the RANTES increases by all three stimuli. A human enterocyte line was similarly examined, and both NF-B and JNK regulate IL-1-induced RANTES secretion. We conclude that in IEC-18, IL-1-induced increases in mRNA for MIP-2, MCP-1, and iNOS are NF-B-dependent, whereas regulation of RANTES mRNA is independent of NF-B but is positively regulated by JNK. IL-1-induced mRNA increases in COX-2 mRNA are both NF-B- and MAPK-independent but the translation of COX-2 protein is NF-B-dependent. This pattern of signaling due to a single stimulus exposed the complexities of regulating inflammatory genes in IEC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Broad Medical Research Foundation, Inflammatory Bowel Disease grants program, and the Natural Sciences and Engineering Research Council of Canada.

² Current address: Department of Anatomical Pathology, MacKenzie Building, Queen Elizabeth II Health Sciences Centre, 5788 University Avenue, Halifax B3H 1V8, Nova Scotia, Canada.

³ Address correspondence and reprint requests Dr. Andrew W. Stadnyk, Mucosal Immunology Research, Izaak Walton Killam Health Centre, 5850 University Avenue, Halifax B3K 3R6, Nova Scotia, Canada. E-mail address: astadnyk{at}dal.ca

⁴ Abbreviations used in this paper: IEC, intestinal epithelial cell; COX-2, cyclooxygenase-2; IBD, inflammatory bowel disease; iNOS, inducible NO synthase.

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