Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

Li, Heng; Zuo, Jian‐Ping; Tang, Wei

doi:10.3389/fphar.2018.01048

Cited by 354 publications

(314 citation statements)

References 160 publications

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“…PDE4‐mediated PKA–CREB signalling pathways are closely related to MAPK and NF‐κB pathways in many inflammatory conditions (Li et al, ). In our model, Western blot assay showed that DSS treatment increased the phosphorylation of p38, ERK, JNK, and MEK1/2 and treatment with apremilast blocked these phosphorylations (Figure f).…”

Section: Resultsmentioning

confidence: 99%

“…3.9 | Apremilast restrained the activation of NF-κB-, MAPK-, PI3K-AKT-mTOR-, and JAK-STAT-SOCSmediated signalling pathways PDE4-mediated PKA-CREB signalling pathways are closely related to MAPK and NF-κB pathways in many inflammatory conditions (Li et al, 2018). In our model, Western blot assay showed that DSS treatment Figure 6f).…”

Section: Apremilast Down-regulated the Expression Of Pde4 Isoformsmentioning

confidence: 99%

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

Chen

Feng

et al. 2019

British J Pharmacology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Apremilast Down-regulated the Expression Of Pde4 Isoformsmentioning

confidence: 99%

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

Chen

Feng

et al. 2019

British J Pharmacology

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“…Crisaborole, but not vehicle, significantly inhibited inflammatory genes known to be induced through degradation of cAMP by PDE4 at day 8, day 15, or both time points. [46][47][48][49][50] (Fig 8, A) and ISGA scores (Fig 8, B). C, Heat map of Spearman correlation matrix of measured values at day 15.…”

Section: Discussionmentioning

confidence: 98%

“…Crisaborole induced modulation of some cAMP-regulated genes, generally to a greater and more significant extent than vehicle (see Fig E4 in this article's Online Repository at www.jacionline.org). [46][47][48][49][50][51]…”

Section: Crisaborole Modulates Inflammatory Markers In Ad Lesionsmentioning

confidence: 99%

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Bissonnette

Pavel

Diaz

et al. 2019

Journal of Allergy and Clinical Immunology

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Downregulated Skin Biomarkers Upregulated Crisaborole Vehicle Crisaborole Day 15 Day 8 Day 1 Day 15 Day 8 Day 1 Vehicle Day 1 NL CRISABOROLE AND ATOPIC DERMATITIS SKIN BIOMARKERS: AN INTRAPATIENT RANDOMIZED TRIAL 2 AD lesions of identical severity were randomized intrapatient to crisaborole or vehicle and biopsied at days 1, 8, and 15 (including Th2 and Th17/Th22 axes) and improved barrier function NL skin biopsied at day 1 AD, atopic dermatitis; NL, nonlesional; Th, helper T cellBackground: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-tomoderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n 5 40) with mild-to-moderate AD. Methods: Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.

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“…[250][251][252] There also appears to be a common link emerging between PDE4I and IL-23. Several diseases report efficacy of both apremilast and IL-12/23 blockers, such as psoriasis, Behcet's disease, IBD, and hidradenitis suppurativa [253][254][255][256] Of note, both apremilast and IL-12/IL-23 blockers failed to show efficacy in both RA and AS, suggesting apremilast mode of action may mediated through IL-23 downregulation. The potential benefit of apremilast on enthesitis in PsA patients has also been evaluated with improvements in enthesitis scores.…”

Section: Evidence Of Pathogenic Role Of Il-23 In Enthesitis From CLmentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

Cited by 354 publications

References 160 publications

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

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

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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