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Localized Delivery of Interferon-beta by Lactobacillus Exacerbates Experimental Colitis

  1. Author:
    McFarl, A. P.
    Savan, R.
    Wagage, S.
    Addison, A.
    Ramakrishnan, K.
    Karwan, M.
    Tri, D.
    Young, H. A.

  2. Author Address

    [McFarland, Adelle P.; Savan, Ram; Wagage, Sagie; Addison, Augustina; Ramakrishnan, Karthika; Karwan, Megan; Young, Howard A.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Tri Duong] N Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA.;McFarland, AP, NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA.;YoungHow@mail.nih.gov
    1. Year: 2011
    2. Date: Feb
  2. Journal: Plos One
    1. 6
    2. 2
    3. Pages: 13
  4. Type of Article: Article
  5. Article Number: e16967
  6. ISSN: 1932-6203
  1. Abstract:

    Background: 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-beta) 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-beta therapy for multiple sclerosis or hepatitis. Methodology/Principal Findings: To investigate the effects of local administration of IFN-beta on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-beta (La-IFN-beta). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-beta increased sensitivity to DSS. Analysis showed colitic mice pretreated with L alpha-IFN-beta had increased production of TNF-alpha, IFN-gamma, 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-beta. Similarly, bone marrow-derived DCs matured with La-IFN-beta experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs. Conclusions/Significance: 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-b 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.

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External Sources

  1. View Full Text
  2. DOI: 10.1371/journal.pone.0016967
  3. View record in Web of Science®
  4. WOS: 000287482800024

Library Notes

  1. Fiscal Year: FY2010-2011
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