Background
The treatment of nucleotide-binding domain and leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome-mediated pediatric inflammatory diseases is challenging. Here we studied whether cyclic adenosine monophosphate (cAMP) elevator forskolin could attenuate the nigericin-induced NLRP3-inflammasome activation and interleukin-1β (IL-1β) secretion in human macrophages.
Conclusions
Forskolin inhibits the NLRP3 inflammasome activation and the secretion of mature IL-1β, in human macrophages. Forskolin and other cAMP elevator drugs could represent a novel approach for treatment of diseases associated with excessive inflammasome activation, like pediatric inflammatory diseases.
Methods
The proteins and messenger RNA (mRNA) levels of inflammasome structural proteins and proinflammatory cytokines were measured in forskolin-stimulated nigericin-activated human THP-1 macrophages and primary macrophages.
Results
Activation of THP-1 macrophages with nigericin increased the mRNA expression of NLRP3, IL-1β, and caspase-1 (P < 0.01). Forskolin stimulation had no effect on the mRNA expression of NLRP3, caspase-1, or IL-1β in nigericin-activated cells (P > 0.05), while their protein levels were significantly decreased (P < 0.05). Forskolin-mediated increase in cytoplasmic cAMP in non-activated cells was attenuated in nigericin-activated macrophages (P < 0.05). Basal IL-1β secretion increased from 584 to 2696 pg/mL (P < 0.01) in nigericin-activated macrophages; forskolin dose-dependently reduced the nigericin-induced secretion of mature IL-1β (P < 0.01). Forskolin also inhibited the IL-1β secretion from activated human primary macrophages. Conclusions: Forskolin inhibits the NLRP3 inflammasome activation and the secretion of mature IL-1β, in human macrophages. Forskolin and other cAMP elevator drugs could represent a novel approach for treatment of diseases associated with excessive inflammasome activation, like pediatric inflammatory diseases.