Mediation of aldose reductase in lipopolysaccharide-induced inflammatory signals in mouse peritoneal macrophages

Abstract

Aldose reductase (AR; AKR1B1) a member of aldoketo reductase super family, that we had shown earlier mediates cytotoxic signals induced by high glucose, cytokines and growth factors, also mediates the inflammatory signals induced by Gram-negative bacterial endotoxin, lipopolysaccharide (LPS). Inhibition of AR by three distinct AR inhibitors sorbinil, tolrestat or zopolrestat suppressed the LPS-induced production of inflammatory cytokines such as TNF-α, IL-6, IL-1β, IFN-γ, and chemokine MCP-1 in murine peritoneal macrophages. Inhibition of AR also prevented the production of nitric oxide, and prostaglandin E2 and expression of iNOS and Cox-2 proteins. The LPS-induced DNA binding activity of NF-κB and AP1 were significantly inhibited by AR inhibitors, and this effect was mediated through the inhibition of phosphorylation of IκB-α, IKK α/β and PKC. These results suggest the therapeutic use of AR inhibitors as anti-inflammatory drugs.

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

“…24 However, exposure of macrophages to oxLDL under the conditions applied in this study did not result in increased gene expression of inflammatory mediators like tumor necrosis factor (TNF)-␣, interleukin (IL)-6, or IL-1␤ (supplemental Figure III). oxLDL has been described to increase production of reactive oxygen species in macrophages.…”

Inhibition of protein kinase C βII downregulates tristetraprolin expression in activated macrophages

“…cPKCs may upregulate inflammatory genes by activating inflammatory transcription factors NF-κB and AP-1 [22,26,27]. The present results suggest also an inhibitory effect of mRNA stability by upregulating TTP and thus serving as a possible anti-inflammatory feed-back mechanism.…”

“…cPKC isoenzymes may regulate the expression of inflammatory genes by regulating the activation of transcription factors NF-kB and AP-1 [26,27]. PKC may also be involved in the regulation of mRNA stability of inflammatory genes if it regulates the expression of TTP.…”

Amelioration of Experimental Autoimmune Uveoretinitis by Aldose Reductase Inhibition in Lewis Rats

“…Nevertheless, from the evidence we have observed in our other studies, [57][58][59] it can be stated that oxidative stress-induced peroxidation of membrane lipids generates lipid-derived aldehydes that, along with their glutathione conjugates, are reduced by AR to their respective lipid alcohols, which in turn have been shown to activate redox signaling, cause inflammation, and add to the already prevailing oxidative stress. This starts a cycle of events that leads to disease establishment and progression.…”