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.
Highlights
Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that predominantly affects women
Downstream receptor activation, intracellular signalling is regulated by cyclic nucleotide phosphodiesterase families (PDE1 to PDE11) that hydrolyze Cyclic AMP (cAMP) and cGMP as a feedback mechanism to return to basal levels, mediating cAMP-dependent and cGMPdependent protein kinase activation [4]
Evolution with disease progression of cAMP-PDE activities in the kidneys of MRL/lpr mice cAMP-PDE activities were assessed in the kidneys of MRL/lpr lupus-prone mice at two time points of the disease progression, namely at 8 weeks, before major changes in survival rate, proteinuria and serum anti-double-stranded DNA antibody levels occur, and at 18 weeks, characterized in this strain by high levels of proteinuria present in 70% of mice and serum anti-DNA antibodies occurring in 90% of animals [12]
Summary
Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that predominantly affects women. The prevalence of lupus in the UK ranges from 40 cases per 100,000 people among northern Europeans to more than 200 cases per 100,000 people in the black population [1]. This inflammatory disease is characterized by the presence of antidouble stranded DNA marker antibodies in the serum of patients and by characteristic lupus nephropathy inducing chronic renal failure. Among PDEs, the members of the PDE4 family (PDE4A, 4B, 4C and 4D) hydrolyse cAMP and are mainly present in inflammatory cells [5]. This study was designed for investigating the PDE4 expression and activity in MRL/lpr lupusprone mice and for examining in vivo the effects of PDE4 inhibitors on SLE disease progression
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