Naloxone, an Opioid Antagonist, Inhibits Inflammatory Toll-like Receptor 4 Signaling
Davidson, Matthew D.
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Inflammation is a protective response to pathogens, but can have dangerous immunopathological consequences including shock. One mediator of inflammation is Toll-like receptor 4 (TLR4), which binds Pathogen-Associated-Molecular-Patterns and endogenous ligands related to host damage and repair. TLR4 agonism activates the transcription factor NF-κB, which induces genes encoding proinflammatory cytokines, such as interleukin 8 (IL-8). IL-8 attracts neutrophils and regulates their migration. Lipopolysaccharide (LPS) is a constituent of the outer cell wall of Gram negative bacteria and a potent TLR4 agonist. TLR4 is the sole mediator of the inflammatory response to LPS, making LPS a useful positive control. We investigated inhibition of the LPSinduced, TLR4-mediated, inflammatory response by naloxone in the human monocyte cell line THP-1. THP-1 cells demonstrated dose-dependent IL-8 secretion (32.3 – 1841.8 pg/mL) in response to the known TLR4 agonist LPS. Naloxone alone did not elicit IL-8 secretion (2.94 – 3.59 pg/mL) and showed no interference with IL-8 detection by ELISA. Co-administration of LPS and naloxone greatly reduced LPS-induced-IL-8 secretion. These data provide evidence of a functioning TLR4/NF-κB pathway in THP-1 cells. These data also suggest inhibition of this pathway in THP-1 cells by naloxone in the presence of a known agonist, however, the point of interference remains undetermined. These findings have significant implications for immunological research in THP-1 cells and for the administration of naloxone in immunocompromised individuals.