Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity
| Autor: | Qing Qi, Heng Li, Jianping Zuo, Huimin Lu, Wei Tang, Yuanzhuo Gao, Chunlan Feng, Xiaoqian Yang, Yanwei Wu, Chen Fan, Fenghua Zhu, Pei-Lan He |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Male Chemokine Colon Proinflammatory cytokine 03 medical and health sciences Chemokine receptor Mice 0302 clinical medicine Immune system medicine Mesenteric lymph nodes Animals Humans Colitis Intestinal Mucosa Immunity Mucosal Pharmacology biology business.industry NF-kappa B medicine.disease Ulcerative colitis Research Papers Cyclic Nucleotide Phosphodiesterases Type 4 Thalidomide Isoenzymes Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure RAW 264.7 Cells Cancer research biology.protein Cytokines Colitis Ulcerative Apremilast Phosphodiesterase 4 Inhibitors Caco-2 Cells business Protein Kinases 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 |
| Popis: | Background and purpose Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase-4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill-defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium-induced murine UC. Experimental approach Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4-mediated pathways in colon and macrophages were determined using quantitative real-time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry. Key results Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA-CREB and Epac-Rap1 pathways and subsequently suppressed MAPK, NF-κB, PI3K-mTOR, and JAK-STAT-SOCS3 activation. Conclusion and implications Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation. |
| Databáze: | OpenAIRE |
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