Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.
Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.
Keratoconus, historically viewed as a non-inflammatory disease, is an ectatic corneal disorder associated with progressive thinning of the corneal stroma. Recently, a few inflammatory mediators have been reported to be elevated in the tear fluid of keratoconus patients. Consequently, we investigated a wide range of inflammation regulating cytokines in the tears and sera of keratoconus and control subjects. Interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, interferon (IFN)-γ, chemokine C-C motif ligand 5 (CCL5) and tumor necrosis factor (TNF)-α were tested in tear samples and sera of keratoconus and control individuals by multiplex immuno-bead assays. Selected cytokines were further tested by standard ELISA on pooled tear samples. All cytokines in the sera were generally low, with no significant changes between keratoconus and control subjects. However, in tear fluids, clear differences were detected between the two groups. These differences include increased IL-6, and decreased IL-12, TNF-α, IFN-γ, IL-4, IL-13 and CCL5 in keratoconus compared to control tear fluids. The decreases in IL-12, TNF-α and CCL5 were statistically significant, while the IL-13 decrease was statistically significant in the severe keratoconus group only. IL-17 could not be detected by multiplex immuno-bead assay, but showed an increase in keratoconus by conventional ELISA on a limited number of pooled tear samples. Our findings confirm increased IL-6, but dispute earlier reports of increased TNF-α, and suggest a cytokine imbalance in keratoconus disrupting corneal homeostasis. Moreover, an increase in IL-17 suggests tissue degenerative processes at work, contributing to the thinning and weakening of the corneal connective tissue in keratoconus.
Staphylococcus aureus produces a set of proteins (e.g., staphylococcal enterotoxin A [SEA], SEB, toxic shock syndrome toxin 1 [TSST-1]) which act both as superantigens (SAgs) and toxins. Although their mode of action as SAgs is well understood, little is known about how they enter the body via the intestine and cause food poisoning. To examine this problem we used an in vitro culture system to study the capacity of class II MHC-negative human intestinal epithelial cells (Caco-2) to transcytose several staphylococcal toxins. We found that Caco-2 cells are capable of dosedependent, facilitated transcytosis of SEB and TSST-1, but not SEA. We extended these studies in vivo in mice by showing that ingested SEB appears in the blood more efficiently than SEA. Our data suggest that these toxins can cross the epithelium in an immunologically intact form. These results may have important implications for the pathogenesis of food poisoning.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.