Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity.

Abstract

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.

• Authors: Heng Li, Chen Fan, Chunlan Feng, Yanwei Wu, Huimin Lu, Peilan He, Xiaoqian Yang, Fenghua Zhu, Qing Qi, Yuanzhuo Gao, Jianping Zuo, Wei Tang
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 176 Issue 13 Pg. 2209-2226 (07 2019) ISSN: 1476-5381 [Electronic] England
• PMID: 30883697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The British Pharmacological Society.

Chemical References

• Cytokines
• Isoenzymes
• NF-kappa B
• Phosphodiesterase 4 Inhibitors
• Thalidomide
• Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 4
• apremilast

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects)
• Caco-2 Cells
• Colitis, Ulcerative (drug therapy, immunology, metabolism, pathology)
• Colon (drug effects, immunology, metabolism, pathology)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Cytokines (blood)
• Humans
• Immunity, Mucosal (drug effects)
• Intestinal Mucosa (drug effects, metabolism)
• Isoenzymes (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)
• Protein Kinases (metabolism)
• RAW 264.7 Cells
• Signal Transduction (drug effects)
• Thalidomide (analogs & derivatives, pharmacology, therapeutic use)