title: Doxycycline, metronidazole and isotretinoin: Do they modify microRNA/mRNA expression profiles and function in murine T-cells?
abstract: Inflammatory bowel disease (IBD) may develop due to an inflammatory response to commensal gut microbiota triggered by environmental factors in a genetically susceptible host. Isotretinoin (acne therapy) has been inconsistently associated with IBD onset and flares but prior treatment with antibiotics, also associated with IBD development, complicates the confirmation of this association. Here we studied in mice whether doxycycline, metronidazole or isotretinoin induce epigenetic modifications, and consequently change T-cell mRNA expression and/or function directly after treatment and after a 4 week recovery period. Isotretinoin induced IL-10 signaling in Tregs and naive T-cells directly after treatment and reduced effector T-cell proliferation alone and in co-culture with Tregs. Metronidazole activated processes associated with anti-inflammatory pathways in both T-cell subsets directly after the treatment period whereas doxycycline induced an immediate pro-inflammatory expression profile that resolved after the recovery period. Long-term changes indicated an inhibition of proliferation by doxycycline and induction of beneficial immune and metabolic pathways by metronidazole. Persistent alterations in microRNA and mRNA expression profiles after the recovery period indicate that all three medications may induce long-term epigenetic modifications in both T-cell subsets. Yet, our data do not support the induction of a long-term pro-inflammatory phenotype in murine Tregs and naive T-cells.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Becker
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Susan
authors.initials: S
authors.lastname: Bengs
authors.affiliation: Functional Genomics Center Zurich, Zurich, Switzerland.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Aluri
authors.affiliation: Functional Genomics Center Zurich, Zurich, Switzerland.
authors.forename: Lennart
authors.initials: L
authors.lastname: Opitz
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Atrott
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stanzel
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pedro A Ruiz
authors.initials: PAR
authors.lastname: Castro
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frey-Wagner
mesh_terms: D000818:Animals; D004318:Doxycycline / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D015474:Isotretinoin / Q000494:pharmacology*; D008795:Metronidazole / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D008795:Metronidazole; D015474:Isotretinoin; D004318:Doxycycline