K-ATP channel block inhibits the Toll-like receptor 2-mediated stimulation of NF-kappa B by suppressing the activation of Akt, mTOR, JNK and p38-MAPK

Abstract

Changes in the K-ATP channel activity have been shown to regulate inflammation and immune responses. Using human keratinocytes, we investigated the effect of K-ATP channel inhibition on inflammatory mediator production in relation to the Toll like receptor-2-mediated-Akt, mTOR and NF-kappa B pathways, as well as JNK and p38MAPK, which regulate the transcription genes involved in immune and inflammatory responses. 5Hydroxydecanoate (a selective K-ATP channel blocker), glibenclamide (a cell surface and mitochondrial K-ATP channel inhibitor), the Akt inhibitor, rapamycin, Bay 11-7085 and N-acetylcysteine reduced the lipoteichoic acid-or peptidoglycan-induced production of cytokines and chemokines, and production of reactive oxygen species and increased the levels and activities of Kir 6.2, NF-kappa B, phosphorylated-Akt and mTOR, and the activation of JNK and p38-MAPK in keratinocytes. Inhibitors of c-JNK (SP600125) and p38-MAPK (SB203580) attenuated the lipoteichoic acid-or peptidoglycan-induced production of inflammatory mediators, the activation of the JNK and p38-MAPK, and the production of reactive oxygen species in keratinocytes. The results show that K-ATP channel blockers may reduce the bacterial component-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor-2-mediated activation of the Akt, mTOR and NF-kappa B pathways, as well as JNK and p38-MAPK. The suppressive effect of K-ATP channel blockers appears to be achieved by the inhibition of reactive oxygen species production.