title: A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice.
abstract: BACKGROUND
  Chronic inflammation disrupts the colonic epithelial layer in patients afflicted by ulcerative colitis (UC). The use of inhibitors of glycogen synthase kinase three beta (GSK3β) has proven efficacious to mitigate disease symptoms in rodent models of UC by reducing the pro-inflammatory response. Less is known about whether these inhibitors promote colonic regeneration by stimulating proliferation of colonic epithelial cells.
  
  
  OBJECTIVE
  We investigated whether delivery of the GSK3β inhibitor, lithium chloride (LiCl), during the recovery period from acute DSS-induced colitis in mice promoted colonic regeneration and ameliorated disease symptoms. We also tested whether the c-MYC transcription factor (MYC) was involved in this response.
  
  
  METHODS
  Acute colitis was induced by administration of 2.5 % dextran sodium sulfate (DSS) to wild-type C57BL/6 mice for 5 days. During the recovery period, mice received a daily intraperitoneal (IP) injection of LiCl or 1X PBS as a control. Mice were weighed, colon lengths measured, disease activity index (DAI) scores were assessed, and histological analyses were performed on colonic sections. We analyzed transcripts and proteins in purified preparations of the colonic epithelium. We delivered the MYC inhibitor 10058-F4 via IP injection to assess the role of MYC in colonic regeneration.
  
  
  RESULTS
  Lithium treatments promoted recovery from acute DSS-induced damage by increasing expression of Myc transcripts, MYC proteins, and expression of a subset of Wnt/MYC target genes in the colonic epithelium. Inhibiting MYC function with 10058-F4 blunted the lithium response.
  
  
  CONCLUSIONS
  By inducing Myc expression in the colonic epithelium, lithium promotes colonic regeneration after DSS-induced colitis. Therefore, the use of lithium may be of therapeutic value to manage individuals afflicted by UC.
authors: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Dr., H171, Hershey, PA, 17033, USA. wmk113@psu.edu.
authors: Wesley M
authors: WM
authors: Raup-Konsavage
authors: Department of Comparative Medicine, The Pennsylvania State University College of Medicine, 500 University Dr., H171, Hershey, PA, 17033, USA. tcooper@hmc.psu.edu.|Department of Pathology, The Pennsylvania State University College of Medicine, 500 University Dr., H054, Hershey, PA, 17033, USA. tcooper@hmc.psu.edu.
authors: Timothy K
authors: TK
authors: Cooper
authors: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Dr., H171, Hershey, PA, 17033, USA. gsy3@psu.edu.
authors: Gregory S
authors: GS
authors: Yochum
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy; D003106:Colon / Q000187:drug effects*; D016264:Dextran Sulfate / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; D051153:Wnt Proteins; D016264:Dextran Sulfate; D018021:Lithium Chloride
keywords: Colonic regeneration; Glycogen synthase kinase; Lithium; MYC; Ulcerative colitis