These experiments are designed to better understand the nature and consequences of neutrophil interaction with intestinal epithelia as often occurs in the active phase of inflammatory bowed disease. The long range philosophy of this project is to use reductionistic models of neutrophil- epithelial interactions in which mechanisms governing the interactions between these two cell types can be unraveled. Then, in the future, the mechanisms uncovered will be tested to see if similar specific interactions occur in nature. To accomplish this goal we use the human crypt epithelial model T84 since the crypt is the site at which neutrophil-epithelial interactions are most frequently noted in intestinal disease states. Purified human peripheral blood neutrophils will be used as the """"""""model"""""""" inflammatory cell. First, we will pursue findings that indicate that neutrophil-epithelial interactions elicit Cl secretion - the known basis of secretory diarrhea. Specifically, we will examine the regulation of a interactive purine metabolic pathway which appears to exist between intestinal epithelia and neutrophils. Second we will attempt to identify cytokine induced epithelial adhesive ligands for neutrophils which may be responsible for interferon-gamma-modulated neutrophil- epithelial cell interactions. Third, we will examine how direct contact between epithelial basolateral membranes and intraepithelial lymphocytes modulates epithelial function and subsequent neutrophil-epithelial interactions. Lastly, we will examine a natural signal (S. typhimurium) which appears to induce neutrophil transepithelial migration by mechanisms other than classically understood bacterial chemoattractants. Such data will provide insights into mechanisms of neutrophil-intestinal epithelial crosstalk during active inflammation and may thus provide new clues for strategic interference in these often deleterious intercellular interactions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Szeto, Frances L; Sun, Jun; Kong, Juan et al. (2007) Involvement of the vitamin D receptor in the regulation of NF-kappaB activity in fibroblasts. J Steroid Biochem Mol Biol 103:563-6
Duan, Yingli; Liao, Anne P; Kuppireddi, Sumalatha et al. (2007) beta-Catenin activity negatively regulates bacteria-induced inflammation. Lab Invest 87:613-24
Sun, Jun; Fegan, Pamela E; Desai, Anjali S et al. (2007) Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 292:G767-78
Sun, Jun; Kong, Juan; Duan, Yingli et al. (2006) Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab 291:E315-22
Sun, Jun; Hobert, Michael E; Duan, Yingli et al. (2005) Crosstalk between NF-kappaB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 289:G129-37
Sun, Jun; Hobert, Michael E; Rao, Anjali S et al. (2004) Bacterial activation of beta-catenin signaling in human epithelia. Am J Physiol Gastrointest Liver Physiol 287:G220-7
Lin, Patricia W; Simon Jr, Peter O; Gewirtz, Andrew T et al. (2004) Paneth cell cryptdins act in vitro as apical paracrine regulators of the innate inflammatory response. J Biol Chem 279:19902-7
Kucharzik, Torsten; Gewirtz, Andrew T; Merlin, Didier et al. (2003) Lateral membrane LXA4 receptors mediate LXA4's anti-inflammatory actions on intestinal epithelium. Am J Physiol Cell Physiol 284:C888-96
Yan, Yiping; Dempsey, Robert J; Flemmer, Andreas et al. (2003) Inhibition of Na(+)-K(+)-Cl(-) cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res 961:22-31
Gewirtz, Andrew T; Collier-Hyams, Lauren S; Young, Andrew N et al. (2002) Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis. J Immunol 168:5260-7

Showing the most recent 10 out of 42 publications