Dual targeting of NF-κB and JAK-STAT pathways by pinoresinol attenuates IL-6-mediated inflammation in differentiated THP-1 cells

Abstract

Abstract Background: Dysregulated synthesis of IL-6 plays a critical role in inflammation-induced disease pathophysiology. IL-6 is known to induce NF-κB alongside canonical JAK-STAT pathway, indicating the importance of cascade proteins of these two pathways as the targets of anti-inflammatory compounds. Plant-derived phenolic compounds are acknowledged as for their anti-inflammatory efficacies. Here, we report the mechanism of downregulation of NF-κB and JAK-STAT pathways by pinoresinol, a plant lignan, in IL-6-induced differentiated macrophages. Methods and Results: Bioinformatic analysis revealed Pinoresinol, among 100 dietary polyphenols, as the most potent to interact with the proteins in NF-κB and JAK-STAT cascades. In differentiated THP-1 macrophages, Pinoresinol repressed IL-6-mediated activation and nuclear translocation of both NF-κB and STAT3. It also reduced the phosphorylation of IKK and IκBα, and degradation of the latter. Expressions of downstream genes of NF-κB and STAT3 pathways, e.g. IL-1β, TNF-α, and COX-2 were also attenuated following pinoresinol treatment. The polyphenol reduced the IL-6-mediated macrophage adhesion and migration, which was further supported by downregulation of VCAM-1, ICAM-1, MCP-1, MMP9 and MMP2 in pinoresinol-treated cells. Conclusions: Our data confirms that pinoresinol targets NF-κB and JAK-STAT pathways to attenuate IL-6-induced inflammation. It inhibits expression of downstream pro-inflammatory mediators, macrophage adhesion and migration suggesting its potential in anti-inflammatory therapy.