Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.

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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.