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Interleukin-6 (IL-6) is a pleiotropic cytokine that coordinates host immune responses to infection. Though essential to the acute phase response, prolonged IL-6-mediated recruitment of mononuclear cells has been implicated in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, and Crohn’s disease. Accordingly, identifying novel therapeutics that diminish circulating IL-6 levels could benefit individuals suffering from chronic inflammation. In immunocompetent hosts, bacterial lipopolysaccharide (LPS) recognition by toll-like receptor 4 (TLR4) activates the transcription factor NF-κB, driving macrophage production of IL-6. Interestingly, both citrate-stabilized and ‘green’ synthesized gold nanoparticles (AuNPs) have been shown to modulate the cytokine responses of LPS-activated macrophages. Here we demonstrate that AuNPs, synthesized with commercial and locally sourced honey, downregulate LPS-induced macrophage secretion of IL-6. Compared to LPS-only controls, inhibition of IL-6 levels was observed for all three types of honey AuNPs. The effect was likely driven by honey AuNP-mediated perturbation of the TLR4/NF-κB signaling pathway, as evidenced by a reduction in the phosphorylation of IκB. Further investigation into the anti-inflammatory properties of honey AuNPs may yield novel therapeutics for the treatment of chronic inflammation.