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Published on: January 5, 2017
Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal
Heng Li1,2, Yao Zhang3, Moting Liu1,2
1Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis (UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors, to explore the therapeutic capacity in dextran sulfate sodium (DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective cAMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated cAMP-predominant protein kinase A (PKA)-cAMP-response element binding protein (CREB) signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present study revealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.
Insights
Apremilast, a phosphodiesterase-4 (PDE4) inhibitor, effectively treats chronic ulcerative colitis (UC) by restoring gut barrier function and modulating immune responses. This study highlights PDE4 inhibition as a promising therapeutic strategy for UC patients.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Phosphodiesterase-4 (PDE4) hydrolyzes cyclic adenosine monophosphate (cAMP), and its inhibition is explored for inflammatory conditions.
- The role of PDE4 and its inhibitors in chronic ulcerative colitis (UC) pathogenesis and treatment remains underexplored.
Purpose of the Study:
- To investigate the therapeutic potential of apremilast, a PDE4 inhibitor, in a dextran sulfate sodium (DSS)-induced murine model of chronic UC.
- To elucidate the underlying mechanisms of PDE4 inhibition in ameliorating UC symptoms.
Main Methods:
- Induction of chronic UC in mice using DSS.
- Administration of apremilast to assess therapeutic effects.
- Analysis of PDE4 isoform expression, cAMP signaling pathways (PKA-CREB), gut barrier function, and gut microbiota composition.
Main Results:
- Overexpression of PDE4 isoforms and defective cAMP signaling were observed in inflamed UC tissues.
- Apremilast treatment ameliorated clinical UC symptoms, including mucosal ulcerations and fibrosis.
- Apremilast restored intestinal barrier function, modulated immune cell interactions, and altered gut microbiota profiles.
Conclusions:
- PDE4 inhibition by apremilast offers a viable therapeutic strategy for chronic and relapsing UC.
- Apremilast normalizes cAMP-mediated signaling, enhances gut barrier integrity, and positively influences the gut microbiome in UC.
- Targeting PDE4 represents a promising approach for managing chronic ulcerative colitis.
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