In:
Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 29, No. 8 ( 2023-08-01), p. 1191-1201
Abstract:
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa with increasing prevalence and limited management. Ruxolitinib is a new anti- JAK/STAT3 biologic agent that has shown potential in protecting against colitis. Methods We first constructed an in vivo UC model and an in vitro colonic epithelial cell inflammation model. Ruxolitinib was administered via gavage in mice. After treatment, colon tissues, cells, and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, immunofluorescence staining, quantitative reverse-transcriptase polymerase chain reaction, Western blotting, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining, and cytokine analysis. STAT3 expression was silenced and overexpressed via small interfering RNA and overexpression plasmid transfection, respectively, and quantitative reverse-transcriptase polymerase chain reaction was used to examine the downstream effects. Results Ruxolitinib administration significantly alleviated colitis both in vivo and in vitro, as manifested by reduced body weight loss, shortened colon lengths, relieved disease activity (measured by the disease activity index), and prolonged survival. A mechanistic study showed that ruxolitinib attenuated nuclear factor kappa B–induced inflammation, reduced apoptosis, and ameliorated epithelial barrier leakage, and thereby reduced colitis activity in vivo. STAT3 knockdown partially reversed the protective effect of ruxolitinib against colitis, while STAT3 overexpression exaggerated the reductions in proinflammatory cytokine levels upon ruxolitinib treatment. Conclusions We demonstrate that ruxolitinib alleviates colitis by inhibiting nuclear factor kappa B–related inflammation and apoptosis in addition to restoring epithelial barrier function via STAT3, providing a new strategy for UC treatment.
Type of Medium:
Online Resource
ISSN:
1078-0998
,
1536-4844
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2023
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