title: Localized delivery of interferon-β by Lactobacillus exacerbates experimental colitis.
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-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 the spontaneous development of IBD in patients receiving systemic IFN-β therapy for multiple sclerosis or hepatitis.
  
  
  RESULTS
  To investigate the effects of local administration of IFN-β on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-β (La-IFN-β). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-β increased sensitivity to DSS. Analysis showed colitic mice pretreated with La-IFN-β had increased production of TNF-α, IFN-γ, 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-β. Similarly, bone marrow-derived DCs matured with La-IFN-β experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs.
  
  
  CONCLUSIONS
  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-β 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.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Adelle P
authors.initials: AP
authors.lastname: McFarland
authors.forename: Ram
authors.initials: R
authors.lastname: Savan
authors.forename: Sagie
authors.initials: S
authors.lastname: Wagage
authors.forename: Augustina
authors.initials: A
authors.lastname: Addison
authors.forename: Karthika
authors.initials: K
authors.lastname: Ramakrishnan
authors.forename: Megan
authors.initials: M
authors.lastname: Karwan
authors.forename: Tri
authors.initials: T
authors.lastname: Duong
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D007370:Interferon Type I / Q000009:adverse effects* / Q000235:genetics* / Q000378:metabolism; D007779:Lactobacillus acidophilus / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D030781:Organisms, Genetically Modified; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D011994:Recombinant Proteins
chemical_list: D007370:Interferon Type I; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D016264:Dextran Sulfate