Disease Progression in MRL/lpr Lupus-Prone Mice Is Reduced by NCS 613, a Specific Cyclic Nucleotide Phosphodiesterase Type 4 (PDE4) Inhibitor

Abstract

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC50 = 1.4 nM) than the other subtypes (PDE4A, IC50 = 44 nM; PDE4B, IC50 = 48 nM; and PDE4D, IC50 = 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (Ki = 148 nM) in comparison to rolipram (Ki = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease.

A Novel Subset of Anti-Inflammatory CD138+ Macrophages Is Deficient in Mice with Experimental Lupus

“…It remains unclear whether CD138 is a component of a transcriptional program that dampens inflammatory responses (36) or only a marker for a subset of anti-inflammatory/resolution phase Mϕ. Inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which hydrolyzes cAMP, modulates disease progression in MRL/ lpr lupus mice (71) and the PDE4 inhibitor apremilast is beneficial in human discoid lupus (72). It will be of interest in the future to see if PDE4 inhibitors promote expansion of the CD138 + Mϕ subset via CREB activation.…”

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase Blocks Intracellular TLR Signaling in Chronic Lymphocytic Leukemia and Normal Hematopoietic Cells

“…Abnormal synthesis of pro-inflammatory cytokines has also been observed in monocytes from SLE patients (69). NCS 613, a PDE4 inhibitor, has been reported to reduce disease activity in lupus prone-mice (70). We found that co-treatment with rolipram markedly reduced PBMC IFN-α production stimulated by TLR7 and TLR9 agonists.…”

Advances in targeting cyclic nucleotide phosphodiesterases

“…Given their potent anti-inflammatory effects, PDE4 inhibitors might be useful for treating diseases involving aberrant immune responses, such as atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease and type 1 diabetes 29–31,35,122,123 . As shown in TABLE 4, apremilast — a second-generation PDE4 inhibitor — is in Phase II and Phase III trials for use in psoriasis and psoriatic arthritis 31,123 .…”