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Induction of Intestinal Epithelial CelhDerived lntedeuidn-6 by the Mucosal Enteric Pathogen, Salmonella typhi Debra L Weinstein, Barbara L. O'Neill, and Eleanor S. Metcalf Department of Microbiology and Immunology F. Edward He, bert School of Medicine Uniformed Services University of. t.he Health Sciences 4301 Jones Bridge Road Bethesda, MD 20814-4799 Running title: $. typhi induces intestinal epithelial cell-derived IL-6 Corresponding author: Dr. Eleanor S. Metcalf Department of Microbiology and Immunology F. Edward l-l~bert School of Medicine 4301 Jones Bridge Road Bethesda, MD 20814~5799 Telephone: (301) 295-3413 Fax: (301) 295-1545 Electronic mail address: me~calf@usuhsl~,usuhs=r~i[

SUMMARY lnterleukin 6 ilL-6) is a multi-functional cytosine that has been shown to be associated with bot.h systemic and tissue-specific responses within the host. Moreover, IL-6 is produced by both lymphoid and non-lymphoid cells and has been identified as a growth-inducing, growth-inhibiting, and differentiation-inducing factor for these cells. Recent studies of uropathogenic and upper respiratory pathogens have suggested that epithelial cell-derived IL-6 plays a role in mucosal host-parasite interactions. Since many mucosal enteric pathogens enter the host through the distal small intestine, a role for epithelial cell-derived IL-6 in the initial interaction between bacteria and host might also be predicted. However, as yet, no studies have determined whether the Interaction of any bacteria with the epithelial cells that line the small intestine of the host can ~nduce IL-6. To address this issue, we have established an in vitro model to evaluate the capacity of the Gram negative bacterium, Salmonella typhi, to induce IL-6 in the small intestinal epithelial cell line, Int407, and in other intestinal epithelial cell lines. The results demonstrate that both wild type and live, attenuated S. typhf vaccine strains induce small and large intestinal epithelial cells to secrete IL-6, and kinetic analysis suggests that IL- 6 may'be one of the earliest responses following adherence and invasion of enteric organisms. Thus, these studies suggest a physiologic role for epithelial cell-derived IL-6 in'the initial interactions between host and bacZeriu~n in the small intestine. 3