Suppression of NF-κB signaling mitigates polyethylene wear particle-induced inflammatory response.

In end-stage arthritis patients, total joint replacement is a very effective surgical procedure. Nevertheless, the high revision rate after surgery remains a major concern. The wear particles generated from biomaterial-induced tissue responses may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Several important signaling pathways are involved in wear particles induced inflammatory reactions, including the transcription factor NF-κB. We recently reported that RAW264.7 macrophage cell exposure to ultra-high molecular weight polyethylene (UHMWPE) particles significantly increased the NF-κB activity in a generated NF-κB responsive luciferase reporter cell clone. The NF-κB activity induced by UHMWPE particles in a mouse RAW264.7 macrophage cell line, bone marrow derived macrophages, and human THP1 macrophage cell line, were suppressed by double strand decoy oligodeoxynucleotide (ODN) containing an NF-κB binding element. Macrophages exposure to UHMWPE particles with or without endotoxin induced pro-inflammatory cytokine and chemokine expression including TNF-α, MCP1, MIP1α, and others. Finally, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, consequently reducing macrophage recruitment by cellular conditioned medium exposed to wear particles. These findings suggest that local suppression of inflammatory cytokine production via inhibition of NF-κB activity with decoy ODN in total joint replacement patients could potentially be an effective strategy to alleviate wear particle-induced chronic inflammation.