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(American Journal of Pathology. 2001;158:1101-1109.)
© 2001 American Society for Investigative Pathology

Regular Articles

Monocyte/Macrophage Activation by Normal Bacteria and Bacterial Products

Implications for Altered Epithelial Function in Crohn’s Disease

Mehri Zareie^*, Paramjit K. Singh^*, E. Jan Irvine^*, Philip M. Sherman, Derek M. McKay^* and Mary H. Perdue^*

From the Intestinal Disease Research Program,^*
McMaster University, Hamilton; and the Division of Gastroenterology and Nutrition,
Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Intestinal immune cells are less reactive than those in the peripheral blood; however, such cells from patients with Crohn’s disease may be more responsive to bacterial products. Our study examined if nonpathogenic bacteria or lipopolysaccharide (LPS), can affect epithelial function in the presence of monocytes/macrophages. Lamina propria mononuclear cells (LPMCs) and peripheral blood monocytes (PBMs) were obtained from patients with Crohn’s disease and control patients. Filter-grown T84 epithelial monolayers were co-cultured with nonactivated or LPS-activated LPMCs or PBMs for 48 hours. Epithelial secretory [baseline short-circuit current (Isc) and Isc to forskolin] and barrier (transepithelial electrical resistance) parameters were measured in Ussing chambers. LPS-activated PBMs from both controls and patients with Crohn’s disease significantly increased Isc (300%) and reduced transepithelial electrical resistance (40%). Epithelial function was not altered after co-culture with control LPMCs ± LPS. However, LPMCs from patients with Crohn’s disease spontaneously secreted tumor necrosis factor-, and induced epithelial changes similar to those produced by LPS-activated PBMs. Co-culture with control Escherichia coli and PBMs induced comparable changes in epithelial physiology, which were abrogated by anti-tumor necrosis factor- antibody. We conclude that LPMCs of patients with Crohn’s disease are spontaneously activated, possibly by gram-negative luminal bacteria, and can directly cause significant alterations in epithelial ion transport and barrier functions.

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