Production of LPS-induced inflammatory mediators in murine peritoneal macrophages: Neocuproine as a broad inhibitor and ATP7A as a selective regulator

Om V. Patel, William B. Wilson, Zhenyu Qin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Copper chelation regulates the production of inflammatory mediators in vivo during vascular inflammation and atherogenesis. Little is known about how the copper egress pump ATP7A regulates the production of these mediators. In this study, we isolated ATP7A deficient macrophages (MΦ) from the peritoneal cavity of blotchy mice and identified the lipopolysaccharide (LPS)-induced inflammatory mediators that were altered by ATP7A deficiency. These results were compared with the effect of neocuproine (a copper chelator) treatment on both ATP7A deficient and control MΦ. Seven of the 24 inflammatory mediators examined in this study had significant changes in expression in the ATP7A deficient MΦ compared to controls; 16 of these mediators were significantly reduced in MΦ treated with neocuproine compared to controls. Both neocuproine treatment and ATP7A deficiency reduced IFN-γ, MCP-1, MCP-3, and VEGF-A levels. Interestingly, the production of KC/GRO was upregulated by ATP7A deficiency but downregulated by neocuproine treatment. Neocuproine, but not ATP7A deficiency, reduced the production of FGF-9, IL-1α, IL-12p70, IL-2, IL-3, IL-4, IL-6, MIP-1β, MIP-2, RANTES, and TNFα. ATP7A deficiency but not neocuproine treatment reduced IP-10 and MCP-5 levels. In addition, both ATP7A deficiency and neocuproine treatment had no effect on GM-CSF, IL-10, IL-11, IL-7, OSM, and SCF. Together, these findings provide evidence that MΦ ATP7A selectively regulates LPS-induced inflammatory mediators, in part, via modulation of cellular copper availability, whereas neocuproine generally inhibits the production of inflammatory mediators. These results also imply that although copper chelation and ATP7A downregulation may result in different copper concentrations, gradients, and/or distribution in the cells, they may not lead to opposite biological effects on inflammatory mediator production.

Original languageEnglish (US)
Pages (from-to)415-425
Number of pages11
Issue number3
StatePublished - Jun 2013


  • ATP7A
  • Copper
  • Macrophage
  • Neocuprione

ASJC Scopus subject areas

  • Biomaterials
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Metals and Alloys


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