BioMetals

, Volume 26, Issue 3, pp 415–425

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

Article

DOI: 10.1007/s10534-013-9624-4

Cite this article as:
Patel, O.V., Wilson, W.B. & Qin, Z. Biometals (2013) 26: 415. doi:10.1007/s10534-013-9624-4

Abstract

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.

Keywords

Copper Macrophage ATP7A Neocuprione 

Abbreviations

FGF

Fibroblast growth factor

i.p.

Intraperitoneal

IFN

Interferon

IL

Interleukin

IP-10

IFN-γ-inducible protein 10

KC/GRO

Growth-regulated α protein

LPS

Lipopolysaccharide

MCP

Monocyte chemotactic protein

MIP

Macrophage inflammatory protein

Macrophages

NC

Neocuproine

OSM

Oncostatin-M

PMA

Phorbol-12-myristate-13-acetate

RANTES

T-cell-specific protein

SCF

Stem cell factor

SD

Standard deviation

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Vascular Surgery, Department of SurgeryUniversity of Texas Health Science Center at San AntonioSan AntonioUSA

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