Pinoresinol targets NF-kB alongside STAT3 pathway to attenuate IL-6-induced inflammation

Dysregulated synthesis of IL-6 plays a critical role in inflammation-induced disease pathophysiology. IL-6 is known to induce NF-κB along with canonical JAK-STAT pathway, indicating the importance of cascade proteins of these two pathways as the targets of anti-inflammatory compounds. Here, we report the mechanism of downregulation of NF-κB and JAK-STAT pathways by pinoresinol, a plant lignan, in IL6-induced macrophages. Bioinformatic analysis revealed Pinoresinol, among 100 dietary polyphenols, as the most potent candidate to interact with the proteins in NF-κB and JAK-STAT pathways. Pinoresinol significantly abrogated IL-6-mediated activation of p65 NF-κB and STAT3 and their nuclear translocation in differentiated THP-1 cells. Remarkably, pinoresinol attenuated IL-6-mediated activation of NF-κB regulators, IKK and IκB-α and the degradation of the latter suggesting its critical role in inhibition of NF-kB pathway. The expressions of downstream genes of the two pathways, e.g. IL-1β, TNF-α, and COX-2 were also inhibited by pinoresinol. The polyphenol treatment also reduced the IL-6-mediated macrophage adhesion and migration, which was supported by the downregulation of VCAM-1, ICAM-1, MCP-1, MMP-9 and MMP-2. Our study highlights the mechanism of anti-inflammatory efficacy of pinoresinol in IL-6-induced differentiated macrophages.