SOD3 Reduces Inflammatory Cell Migration by Regulating Adhesion Molecule and Cytokine Expression

Abstract

Inflammatory cell migration characteristic of ischemic damages has a dual role providing the tissue with factors needed for tissue injury recovery simultaneously causing deleterious development depending on the quality and the quantity of infiltrated cells. Extracellular superoxide dismutase (SOD3) has been shown to have an anti-inflammatory role in ischemic injuries where it increases the recovery process by activating mitogen signal transduction and increasing cell proliferation. However, SOD3 derived effects on inflammatory cytokine and adhesion molecule expression, which would explain reduced inflammation in vascular lesions, has not been properly characterized. In the present work the effect of SOD3 on the inflammatory cell extravasation was studied in vivo in rat hind limb ischemia and mouse peritonitis models by identifying the migrated cells and analyzing SOD3-derived response on inflammatory cytokine and adhesion molecule expression. SOD3 overexpression significantly reduced TNFα, IL1α, IL6, MIP2, and MCP-1 cytokine and VCAM, ICAM, P-selectin, and E-selectin adhesion molecule expressions in injured tissues. Consequently the mononuclear cell, especially CD68+ monocyte and CD3+ T cell infiltration were significantly decreased whereas granulocyte migration was less affected. According to our data SOD3 has a selective anti-inflammatory role in ischemic damages preventing the migration of reactive oxygen producing monocyte/macrophages, which in excessive amounts could potentially further intensify the tissue injuries therefore suggesting potential for SOD3 in treatment of inflammatory disorders.

Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation

“…Increase in the SOD activity in this group may suggest the indomethacin induced protective mechanism attempting to counteract the inflammatory condition by the recruitment of protective cytokines and adhesion molecules at the site of inflammation [35].…”

Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases

“…These responses are associated with reduced adhesion molecule and cytokine expression and inflammatory cell recruitment (130) in ischemic tissues in hindlimb ischemia model. Consistent with SOD3 2/2 mice, SOD1-deficient mice show impaired neovascularization, as assessed by reduction of blood flow recovery and capillary density in ischemic muscle (80).…”

Anti‐inflammatory effects of tobramycin and a copper–tobramycin complex with superoxide dismutase‐like activity

“…However, we found that although tobramycin significantly inhibited neutrophil migration at low concentrations, it was more effective as an inhibitor of T-cell migration. This may be because neutrophils do not use the VCAM-1 pathway of cell adhesion and endothelial activation previously reported (Laurila et al, 2009), but utilize the ICAM-1-dependent pathway in which no role for endothelial NADPH oxidase has been described (reviewed in Muller, 2011). We speculate that the lack of effect of tobramycin at the highest concentration reflects competition for endothelial cell uptake between low levels of the contemporaneously formed CuT complex and excess free, uncomplexed, tobramycin for heparan sulphate binding sites.…”

“…Previous reports indicated free radical scavenging activity of copper complexed to a number of ligands (reviewed in Milanino and Buchner, 2006), and an inhibitory effect of extracellular SOD (SOD3) on T-cell migration in animal models in vivo (Laurila et al, 2009). We therefore considered the possibility that inhibition of T-cell transendothelial migration was mediated by tobramycin binding copper in situ to generate a complex with SOD-like activity.…”

“…However, many drugs that bind copper form complexes with SOD-like activity (Milanino and Buchner, 2006). Lymphocyte transendothelial migration was previously reported to be dependent on VCAM-1-dependent activation of endothelial cell NADPH oxidase, the generation of superoxide anions and low concentrations of hydrogen peroxide (Cook-Mills, 2006) and was inhibited in vitro and in vivo by the antioxidants bilirubin and SOD3 (Cook-Mills, 2006;Laurila et al, 2009). Our data indicate that tobramycin chelates copper present in the cells and/or media to generate a SOD-like complex, with the potential to limit the expression of a wide range of adhesion molecules and inflammatory cytokines that are regulated by the NF-kB pathway (Milanino and Buchner, 2006;Laurila et al, 2009) and limit T-cell migration (Cook-Mills, 2006;Milanino and Buchner, 2006).…”