A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice

Wesley M. Raup-Konsavage, Timothy Cooper, Gregory Yochum

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. Aims: 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.

Original languageEnglish (US)
Pages (from-to)410-422
Number of pages13
JournalDigestive Diseases and Sciences
Volume61
Issue number2
DOIs
StatePublished - Feb 1 2016

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Dextran Sulfate
Lithium
Regeneration
Colitis
Epithelium
Ulcerative Colitis
Lithium Chloride
Intraperitoneal Injections
Glycogen Synthase Kinases
Inbred C57BL Mouse
Rodentia
Colon
Proteins
Transcription Factors
Epithelial Cells
Inflammation
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Gastroenterology

Cite this

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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. Aims: 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.",
author = "Raup-Konsavage, {Wesley M.} and Timothy Cooper and Gregory Yochum",
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A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice. / Raup-Konsavage, Wesley M.; Cooper, Timothy; Yochum, Gregory.

In: Digestive Diseases and Sciences, Vol. 61, No. 2, 01.02.2016, p. 410-422.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice

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AU - Cooper, Timothy

AU - Yochum, Gregory

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N2 - 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. Aims: 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.

AB - 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. Aims: 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.

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