NCS 613 exhibits anti-inflammatory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NF-κB signalling pathways while reducing proinflammatory cytokine production

Abstract

Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that evolves into progressive and chronic inflammation of multiple joints and organs. Phosphorylation and activation of p38 MAPK, along with the resulting overproduction of interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α is a hallmark of inflammatory disorders. Here, we investigated the anti-inflammatory pathway modulated by NCS 613, a specific PDE4 inhibitor, on human peripheral blood mononuclear cells (PBMCs) from 5 healthy donors and 12 SLE patients. PDE4 subtypes, p38 MAPK, and IκBα protein levels were analyzed by Western blot, while NF-κB and PDE4B immunostaining was assessed in control and lipopolysaccharide (LPS) -pretreated PBMCs. Proinflammatory cytokines were quantified by ELISA, while IL-1β mRNA was resolved by RT–qPCR. NCS 613 treatment decreased PDE4B and upregulated PDE4C in human PBMCs from healthy donors and SLE patients. LPS stimulation increased p38 MAPK phosphorylation and NF-κB translocation to the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restored IκBα detection levels in human PBMCs from both healthy donors and SLE patients. This compound also abolished LPS-induced inflammation in PBMCs by reducing IL-6, IL-8, and TNF-α cytokines. NCS 613 is a small molecule displaying anti-inflammatory properties that may provide an alternative or complementary strategy for SLE management.