Toll‐Like Receptors in the Mechanism of Hexabromocyclododecane‐Induced Production of Pro‐Inflammatory Cytokines

Hexabromocyclododecane (HBCD), a brominated flame retardant, has raised increasing health concerns due to its bioaccumulation in human tissues and its ability to induce proinflammatory cytokines. Interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) are major mediators of inflammation, and their chronic elevation contributes to autoimmune disorders, cardiovascular disease, and cancer. Previous studies have implicated mitogen‐activated protein kinases (MAPKs) as mediators of HBCD‐induced IL‐1β and IL‐6 production. Because MAPKs act downstream of Toll‐like receptors (TLRs)—key inflammatory response regulators, identifying whether TLRs contribute to HBCD‐driven inflammation is essential. This study examined the roles of TLR1/2, TLR2, TLR3, TLR4, and TLR8 in HBCD‐induced IL‐1β, IL‐6, and TNF‐α production in peripheral blood mononuclear cells (PBMCs). PBMCs were pretreated with selective inhibitors targeting TLR1/2 (CUCPT 22), TLR2 (C29), TLR3 (CUCPT 4a), TLR4 (TAK‐242), TLR8 (CUCPT 9a), and MyD88 (TJ‐M2010‐5), followed by exposure to HBCD (1–5 μM). The results indicated that inhibition of TLR4 significantly reduced HBCD‐induced production of all three cytokines, demonstrating its central roles in this response. Blocking TLR8 significantly reduced HBCD‐induced IL‐1β production. In contrast, inhibition of TLR1/2, TLR2, or TLR3 produced no consistent effects on HBCD‐induced cytokine production. Inhibition of the TLR‐associated adaptor protein MyD88 significantly attenuated HBCD‐induced IL‐1β and IL‐6 production, whereas TNF‐α production was not consistently affected. These results further elucidate the mechanism by which HBCD leads to elevation of pro‐inflammatory cytokine production by human immune cells.