S100A8 is induced in macrophages by oxidants and modulates redox responses in inflammation — ASN Events
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  3. S100A8 is induced in macrophages by oxidants and modulates redox responses in inflammation

S100A8 is induced in macrophages by oxidants and modulates redox responses in inflammation (#83)

Kenneth Hsu 1 , Yuka Hiroshima 1 , Yasumi Endoh 1 , Shane R Thomas 2 , Carolyn L Geczy 1
  1. Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, UNSW, SYDNEY, NSW, Australia
  2. Centre for Vascular Research, School of Medical Sciences, University of New South Wales, SYDNEY, NSW, Australia

S100A8 expression is modulated by stressors that promote reactive oxygen species (ROS) generation. Its induction in macrophages activated by TLR-4, -7, and -9 ligands is dependent on IL-10 production. S100A8 participates in the inflammatory response at various levels, including scavenging of oxidants and nitric oxide. Inflammation increases ROS that can mediate cell signaling to control gene expression. Macrophages treated with LPS in vitro produce ROS and induces S100A8. IL-10 and S100A8 induction were both inhibited by the antioxidant N-acetyl-cysteine, the flavoprotein oxidase inhibitor diphenylene iodonium and the NADPH oxidase inhibitor apocynin. The actions of these pharmacological agents on S100A8 gene expression were recapitulated by downregulation of expression of NADPH oxidase 2 using siRNA, and studies with peritoneal macrophages from NADPH oxidase 2 -/- mice. Importantly, although H2O2 and IL-10 did not induce IL-10 or S100A8 individually when combined they promoted strong expression of both genes.

We next examined whether S100A8 modulated genes involved in ROS generation in LPS-mediated lung inflammation. Q-PCR arrays containing 30 redox-related genes, showed that intranasal inhalation of S100A8 directly induced itself and IL-10 in airway epithelial cells, and heme oxygenase-1 and arginase 2 mRNAs. In mice with LPS-induced lung injury pretreated with S100A8 inhalation, mRNA levels of antioxidant defense proteins, including catalase, metallothioneine-1, glutathione peroxidase, glutathione S-transferase and thioredoxin in lung tissue were potentiated, and iNOS was reduced, compared to lungs from mice treated with LPS alone. Modulation by S100A8 was at least partially dependent on its reactive thiol residue. Cys42 to Ala42 mutant of S100A8 did not induce IL-10 in the lung, and effects on antioxidant genes were reduced. We propose a regulatory feedback loop whereby IL-10 and S100A8 levels are influenced by ROS generation to modulate the redox network in resolution of inflammation. 

Support: Funded by grants #630647 and #1027189, NHMRC Australia.