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

Abstract

Abstract Objective Activation of NF-κB alongside STAT3 by IL-6 plays major role in inflammation-induced disease pathophysiology. Here, we report the mechanism of downregulation of NF-κB and JAK-STAT pathways by pinoresinol in IL6-induced macrophages. Methods Bioinformatic analysis screened Pinoresinol, among 100 dietary polyphenols, as the most potent to interact with the proteins in NF-κB and JAK-STAT cascades. The effect of pinoresinol on IL-6-activated p65 NF-κB and STAT3 and their regulators was studied by immunoblotting. Localization of the transcription factors were investigated by immunofluorescence and fractionation studies. Effect of pinoresinol on the downstream genes of the NF-κB and JAK-STAT pathways was studied by RT-PCR or immunoblotting. Biological implication this inhibition was shown by attenuation of cellular adhesion and migration. Results Pinoresinol repressed IL-6-mediated activation and nuclear translocation of both p65 NF-κB and STAT3. It reduced the phosphorylation of IKK and IκB-α, and degradation of the latter. The expressions of downstream genes 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 supported by downregulation of VCAM-1, ICAM-1, MCP-1, MMP-9 and MMP-2 in pinoresinol-treated cells. Conclusion Pinoresinol targets NF-κB and JAK-STAT pathways to attenuate IL-6-induced inflammatory condition which highlights its potential as a candidate for anti-inflammatory therapy.