Mechanistic investigation of clarithromycin in ulcerative colitis involving Kv1.3 downregulation and modulation of the Th17/Treg balance
4 affiliations
- 1College of Pharmacy, Xinjiang Medical University
- 2Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Xinjiang Medical University
- 3Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Xinjiang Medical University
- 4Charles E. Schmidt College of Science, Florida Atlantic University
Abstract
Introduction: Present therapies for ulcerative colitis (UC) frequently encounter challenges due to medication resistance and side effects, underscoring the necessity to discover secure and efficacious therapeutic targets. Clarithromycin (CLA), a macrolide antibiotic, has not been fully characterized with respect to its anti-inflammatory mechanisms and therapeutic potential in UC.
Methods: An LPS-induced cellular inflammation model, an LPS-induced acute colitis model in mice, and a DSS-induced rat colitis model were established, with control, model, and CLA-treated groups. The anti-inflammatory, intestinal mucosal-protective, and immunomodulatory effects of CLA were evaluated using CCK-8 assays, ELISA, RT-qPCR, hematoxylin and eosin staining, immunohistochemistry, and flow cytometry. Kv1.3 protein expression was evaluated using immunofluorescence and Western blot techniques, while molecular docking and molecular dynamics simulations were conducted to explore the possible interaction between CLA and Kv1.3.
Results: CLA significantly attenuated the LPS-induced reduction in cell viability in vitro and decreased IL-6 and TNF-α levels in cell culture supernatants and mouse serum. In vivo , CLA ameliorated elevated disease activity index scores, colon shortening, increased intestinal permeability, and histopathological damage. Immunohistochemistry further showed that CLA reversed the model-associated upregulation of TLR4 and TLR9 and downregulation of Occludin and ZO-1 in colonic tissue. CLA also significantly downregulated Kv1.3 protein expression in colonic tissue. At the same time, computational analyses suggested that CLA could occupy a putative binding pocket within Kv1.3 and maintain a relatively stable binding conformation during the simulation. In addition, CLA was associated with reduced proportions of DCs subset exhibiting maturation- and homing-related phenotypes, correction of the Th17/Treg imbalance, and reduced proportions of effector T cells in colonic tissue.
Conclusions: Clarithromycin significantly ameliorated DSS-induced ulcerative colitis in rats. This therapeutic effect was accompanied by reduced Kv1.3 expression in colonic tissues, suppression of dendritic cell maturation and intestinal homing, correction of the Th17/Treg imbalance, and decreased intestinal infiltration of effector T cells. Molecular docking and molecular dynamics simulations further suggested a potential interaction between clarithromycin and Kv1.3. These findings provide experimental support for the repurposing of clarithromycin in ulcerative colitis and expression-level evidence supporting Kv1.3 as a potential therapeutic target for UC.
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BibTeX
@article{wu2026mechanistic,
title = {{Mechanistic investigation of clarithromycin in ulcerative colitis involving Kv1.3 downregulation and modulation of the Th17/Treg balance}},
author = {Jiaying Wu and Wen Zhang and Xuwen Mao},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1957785},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957785/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanistic investigation of clarithromycin in ulcerative colitis involving Kv1.3 downregulation and modulation of the Th17/Treg balance
AU - Jiaying Wu
AU - Wen Zhang
AU - Xuwen Mao
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1957785
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957785/full
AB - Introduction: Present therapies for ulcerative colitis (UC) frequently encounter challenges due to medication resistance and side effects, underscoring the necessity to discover secure and efficacious therapeutic targets. Clarithromycin (CLA), a macrolide antibiotic, has not been fully characterized with respect to its anti-inflammatory mechanisms and therapeutic potential in UC. Methods: An LPS-induced cellular inflammation model, an LPS-induced acute colitis model in mice, and a DSS-induced rat colitis model were established, with control, model, and CLA-treated groups. The anti-inflammatory, intestinal mucosal-protective, and immunomodulatory effects of CLA were evaluated using CCK-8 assays, ELISA, RT-qPCR, hematoxylin and eosin staining, immunohistochemistry, and flow cytometry. Kv1.3 protein expression was evaluated using immunofluorescence and Western blot techniques, while molecular docking and molecular dynamics simulations were conducted to explore the possible interaction between CLA and Kv1.3. Results: CLA significantly attenuated the LPS-induced reduction in cell viability in vitro and decreased IL-6 and TNF-α levels in cell culture supernatants and mouse serum. In vivo , CLA ameliorated elevated disease activity index scores, colon shortening, increased intestinal permeability, and histopathological damage. Immunohistochemistry further showed that CLA reversed the model-associated upregulation of TLR4 and TLR9 and downregulation of Occludin and ZO-1 in colonic tissue. CLA also significantly downregulated Kv1.3 protein expression in colonic tissue. At the same time, computational analyses suggested that CLA could occupy a putative binding pocket within Kv1.3 and maintain a relatively stable binding conformation during the simulation. In addition, CLA was associated with reduced proportions of DCs subset exhibiting maturation- and homing-related phenotypes, correction of the Th17/Treg imbalance, and reduced proportions of effector T cells in colonic tissue. Conclusions: Clarithromycin significantly ameliorated DSS-induced ulcerative colitis in rats. This therapeutic effect was accompanied by reduced Kv1.3 expression in colonic tissues, suppression of dendritic cell maturation and intestinal homing, correction of the Th17/Treg imbalance, and decreased intestinal infiltration of effector T cells. Molecular docking and molecular dynamics simulations further suggested a potential interaction between clarithromycin and Kv1.3. These findings provide experimental support for the repurposing of clarithromycin in ulcerative colitis and expression-level evidence supporting Kv1.3 as a potential therapeutic target for UC.
SN - 1664-3224
ER -