Piperine suppresses M1 phenotype and induces indoleamine 2,3-dioxygenase gene in LPS-stimulated murine macrophage cell line.

OBJECTIVE: Activated macrophages play important roles during immune responses by polarizing into M1 and M2 subsets and overproducing several mediators such as nitric oxide (NO), pro- and anti-inflammatory cytokines, and indoleamine 2,3-dioxygenase (IDO). This study aims to investigate the possible effects of piperine, a major component of the pepper plant, on the expression of M1 and M2 macrophage markers.

RESULTS: Piperine dose-dependently decreased iNOS gene expression and NO level in LPS-stimulated macrophages. Additionally, at concentrations of 1-20 µg/ml, it significantly suppressed the production and/or gene expression levels of proinflammatory M1-related cytokines. Its effects on cytokine genes were dose-dependent, and reduced IL-1β, TNF-α, and IFN-γ expression (17 ± 11.8, 1.33 ± 0.76, and 25.4 ± 5.2 fold, respectively, compared with LPS-stimulated cells). Piperine at 1 µg/ml didn't affect the IL-10 gene but significantly increased IDO1 (from 8.4 ± 0.24-fold in LPS-treated cells to 28.3 ± 5.3-fold in piperine-treated cells), and decreased IL-4 gene expressions at the higher concentrations. Dexamethasone (a glucocorticoid anti-inflammatory drug) reduced most mediators but did not affect the IDO gene. Our data demonstrate that piperine dose-dependently inhibits M1-macrophages and upregulates IDO1 at low concentration, a unique mechanism of action, positioning it as a multifaceted therapeutic candidate for inflammatory conditions.