Toll‐Like Receptors in Pentachlorophenol‐ and Dibutyltin‐Induced Production of Pro‐Inflammatory Cytokines, Interleukin (IL)‐1β, and IL‐6, by Human Immune Cells

ABSTRACT Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin‐1 beta (IL‐1β) and IL‐6 are pro‐inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL‐1β and IL‐6 by immune cells in a MAP kinase (MAPK) dependent process. Toll‐like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP‐induced production of IL‐1β and IL‐6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT‐induced IL‐6 production depends on TLR1/2, whereas IL‐1β production does not. Blocking the TLR‐linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL‐1β and IL‐6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro‐inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.