Mechanisms of chemokine responses by polycyclic aromatic hydrocarbons in bronchial epithelial cells: Sensitization through toll-like receptor-3 priming

We have previously observed that 1-nitropyrene (1-NP) and its amine metabolite 1-aminopyrene (1-AP) induce differential chemokine responses in human bronchial epithelial cells (BEAS-2B) characterized by maximum responses for CXCL8 (IL-8) and CCL5 (RANTES), respectively. In the present study, we further explored the effects of 1-NP and 1-AP on chemokine responses. The results suggest that the differential effect of 1-NP and 1-AP on CXCL8 and CCL5 in BEAS-2B cells was mainly related to effects at higher concentrations, which in the case of 1-NP seemed to be linked to ROS-formation and/or metabolic activation by CYP-enzymes. However, at a low concentration (1 μM) where neither 1-NP, 1-AP nor unsubstituted pyrene had any effect on chemokine responses, we found that all three PAHs potentiated CXCL8 and CCL5 responses induced by the TLR3 ligand polyinosinic:polycytidylic acid (Poly I:C) in BEAS-2B cells. As neither benzo[a]pyrene nor β-naphthoflavone induced a similar effect in Poly I:C-primed cells, the response seemed independent of aryl hydrocarbon receptor-mediated mechanisms. The results show that priming cells with an inflammogenic stimuli like Poly I:C sensitizes the cells toward additional pro-inflammatory effects of certain PAHs. The study underscores that testing on healthy cells or animals may not be sufficient to fully evaluate chemokine responses and the pro-inflammatory potential of organic chemicals.

► At 10–20 μM pyrene, 1-NP and 1-AP induced CXCL8/CCL5 differentially in BEAS-2B cells.
► TLR3-priming sensitized cells toward pro-inflammatory effects of PAHs.
► At 1 μM 1-NP, 1-AP and Pyrene enhanced TLR3-mediated CXCL8/CCL5 to a similar extent.
► B[a]P did not affect CXCL8/CCL5 responses indicating AhR-independent mechanisms.
► Healthy cells may not be sufficient to evaluate the proinflammatory potential of PAHs.