TY - JOUR
T1 - Genetic and Small-Molecule Modulation of Stat3 in a Mouse Model of Crohn’s Disease
AU - Robinson, Prema
AU - Magness, Emily
AU - Montoya, Kelsey
AU - Engineer, Nikita
AU - Eckols, Thomas K.
AU - Rodriguez, Emma
AU - Tweardy, David J.
N1 - Funding Information:
This work was supported in part by NIH grant R03 AI099405 (PR), a start-up grant from the Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas (PR), and National Cancer Institute (NCI) PREVENT Program 75N91019D00021 (DJT;PR).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/12
Y1 - 2022/12
N2 - Crohn’s disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆β/∆β), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆β/∆β transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4+ T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.
AB - Crohn’s disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆β/∆β), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆β/∆β transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4+ T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.
KW - Crohn’s disease
KW - inflammatory bowel disease
KW - STAT3
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U2 - 10.3390/jcm11237020
DO - 10.3390/jcm11237020
M3 - Article
C2 - 36498596
AN - SCOPUS:85143627103
SN - 2077-0383
VL - 11
JO - Journal of Clinical Medicine
JF - Journal of Clinical Medicine
IS - 23
M1 - 7020
ER -