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Monocyte Chemoattractant Protein-1 Production by Intestinal Myofibroblasts in Response to Staphylococcal Enterotoxin A: Relevance to Staphylococcal Enterotoxigenic Disease¹

Irina V. Pinchuk^*, Ellen J. Beswick, Jamal I. Saada^*, Giovanni Suarez, John Winston^*, Randy C. Mifflin^*, John F. Di Mari^*, Don W. Powell^*, and Victor E. Reyes^2,

^* Department of Internal Medicine, Departments of Neuroscience and Cell Biology, Departments of Microbiology and Immunology, and Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555

Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3- to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.

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 work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK55783), the John Sealy Memorial Endowment Fund, the University of Texas Medical Branch, Gastrointestinal Research Interdisciplinary Program, the James W. McLaughlin Endowment Fund, and the Gulf Coast Digestive Diseases Center (DK56338).

² Address correspondence and reprint requests to Dr. Victor E. Reyes, University of Texas Medical Branch, Children’s Hospital, Room 2.300, 301 University Boulevard, Galveston, TX 77555. E-mail address: vreyes{at}utmb.edu

³ Abbreviations used in this paper: SEA, staphylococcal enterotoxin A; SEB, staphylococcal enterotoxin B; GI, gastrointestinal; IMF, intestinal myofibroblast; AF, Alexa Fluor; MFI, mean fluorescence intensity; TER, transepithelial resistance; RT, reverse transcription; C_T, cycle threshold.