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Localized delivery of interferon-? by Lactobacillus exacerbates experimental colitis.

ABSTRACT: There have been conflicting reports of the role of Type I interferons (IFN) in inflammatory bowel disease (IBD). Clinical trials have shown potent efficacy of systemic interferon-beta (IFN-?) in inducing remission of ulcerative colitis. Likewise, IFNAR1(-/-) mice display an increased sensitivity to dextran sulfate sodium (DSS)-induced colitis, suggesting Type I IFN play a protective role during inflammation of the gut. Curiously, however, there have also been reports detailing the spontaneous development of IBD in patients receiving systemic IFN-? therapy for multiple sclerosis or hepatitis.To investigate the effects of local administration of IFN-? on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-? (La-IFN-?). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-? increased sensitivity to DSS. Analysis showed colitic mice pretreated with La-IFN-? had increased production of TNF-?, IFN-?, IL-17A and IL-13 by intestinal tissues and decreased regulatory T cells (Tregs) in their small intestine. Examination of CD103(+) dendritic cells (DCs) in the Peyer's patches revealed that IFNAR1 expression was dramatically reduced by La-IFN-?. Similarly, bone marrow-derived DCs matured with La-IFN-? experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs.Our IFNAR1 expression data identifies a correlation between the loss/downregulation of IFNAR1 on DCs and exacerbation of colitis. Our data show that Lactobacillus secreting IFN-? has an immunological effect that in our model results in the exacerbation of colitis. This study underscores that the selection of therapeutics delivered by a bacterial vehicle must take into consideration the simultaneous effects of the vehicle itself.

SUBMITTER: McFarland AP

PROVIDER: S-EPMC3041828 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Localized delivery of interferon-β by Lactobacillus exacerbates experimental colitis.

McFarland Adelle P AP Savan Ram R Wagage Sagie S Addison Augustina A Ramakrishnan Karthika K Karwan Megan M Duong Tri T Young Howard A HA

PloS one 20110218 2

<h4>Background</h4>There have been conflicting reports of the role of Type I interferons (IFN) in inflammatory bowel disease (IBD). Clinical trials have shown potent efficacy of systemic interferon-beta (IFN-β) in inducing remission of ulcerative colitis. Likewise, IFNAR1(-/-) mice display an increased sensitivity to dextran sulfate sodium (DSS)-induced colitis, suggesting Type I IFN play a protective role during inflammation of the gut. Curiously, however, there have also been reports detailing ...[more]

PMID: 21365015

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Dataset Information

Localized delivery of interferon-? by Lactobacillus exacerbates experimental colitis.

Publications

Localized delivery of interferon-β by Lactobacillus exacerbates experimental colitis.

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