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Am J Physiol Cell Physiol (November 9, 2005). doi:10.1152/ajpcell.00308.2005
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Submitted on June 27, 2005
Accepted on November 6, 2005

HMGB1 is Secreted by Immunostimulated Enterocytes and Contributes to Cytomix-induced Hyperpermeability of Caco-2 Monolayers

Shiguang Liu1, Donna B Stolz1, Penny L Sappington1, Carlos A Macias1, Meaghan E Killeen1, Jyrki J Tenhunen1, Russell L Delude1, and Mitchell P Fink1*

1 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

* To whom correspondence should be addressed. E-mail: finkmp{at}ccm.upmc.edu.

High-mobility group box 1 (HMGB1), a cytokine-like pro-inflammatory protein, is secreted by activated macrophages and released by necrotic cells. We hypothesized that immunostimulated enterocytes might be another source for this mediator. Accordingly, Caco-2 cells or primary mouse intestinal epithelial cells (IECs) were incubated with "cytomix" (a mixture of TNF, IL-1{beta}, and IFN-{gamma}) for various periods. HMGB1 in cell culture supernatants was detected by Western blotting and visualized in Caco-2 cells using fluorescence confocal and immuno-transmission electron microscopy. Caco-2 cells growing on filters in diffusion chambers were stimulated with cytomix for 48 h in the absence or presence of anti-HMGB1 antibody, and permeability to fluorescein isothiocyanate-dextran (average molecular weight 4 kDa; FD4) was assessed. Cytomix-stimulated Caco-2 secreted HMGB1 into the apical but not the basolateral compartments of diffusion chambers. Although undetectable at 6 and 12 h after starting incubation with cytomix, HMGB1 was present in supernatants after 24 h of incubation. HMGB1 secretion by Caco-2 monolayers also was induced when the cells were exposed to FSL-1, a Toll-like receptor (Tlr) 2 agonist, or flagellin, a Tlr5 agonist, but not lipopolysaccharide, a Tlr4 agonist. Cytomix also induced HMGB1 secretion by primary IECs. Cytoplasmic HMGB1 is localized within vesicles in Caco-2 cells and is secreted, at least in part, associated with exosomes. Incubating Caco-2 cells with cytomix increased FD4 permeation, but this effect was significantly decreased in the presence of anti-HMGB1 antibody. Collectively, these data support the view that HMGB1 is secreted by immunostimulated enterocytes. This process may exacerbate inflammation-induced epithelial hyperpermeability via an autocrine feedback loop.




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