PMID- 27590200 OWN - NLM STAT- MEDLINE DCOM- 20170223 LR - 20211204 IS - 1432-1912 (Electronic) IS - 0028-1298 (Linking) VI - 389 IP - 12 DP - 2016 Dec TI - Apocynin inhibits Toll-like receptor-4-mediated activation of NF-kappaB by suppressing the Akt and mTOR pathways. PG - 1267-1277 AB - Microbial product lipopolysaccharide has been shown to be involved in the pathogenesis of inflammatory skin diseases. Apocynin has demonstrated to have an anti-inflammatory effect. However, the effect of apocynin on the Toll-like receptor-4-dependent activation of Akt, mammalian target of rapamycin (mTOR), and nuclear factor (NF)-kappaB pathway, which is involved in productions of inflammatory mediators in keratinocytes, has not been studied. Using human keratinocytes, we investigated the effect of apocynin on the inflammatory mediator production in relation to the Toll-like receptor-4-mediated-Akt/mTOR and NF-kappaB pathways, which regulates the transcription genes involved in immune and inflammatory responses. Apocynin, Akt inhibitor SH-5, Bay 11-7085 and N-acetylcysteine each attenuated the lipopolysaccharide-induced production of cytokines, PGE(2), and chemokines, changes in the levels of Toll-like receptor-4, p-Akt, mTOR, and NF-kappaB, and production of reactive oxygen species in keratinocytes. The results show that apocynin appears to attenuate the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-kappaB pathways. The effect of apocynin appears to be attributed to its inhibitory effect on the production of reactive oxygen species. Apocynin appears to attenuate the microbial product-mediated inflammatory skin diseases. FAU - Nam, Yoon Jeong AU - Nam YJ AD - Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea. FAU - Kim, Arum AU - Kim A AD - Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea. FAU - Sohn, Dong Suep AU - Sohn DS AD - Department of Thoracic and Cardiovascular Surgery, Chung-Ang University Hospital, Seoul, 156-755, South Korea. FAU - Lee, Chung Soo AU - Lee CS AD - Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea. leecs@cau.ac.kr. LA - eng PT - Journal Article DEP - 20160902 PL - Germany TA - Naunyn Schmiedebergs Arch Pharmacol JT - Naunyn-Schmiedeberg's archives of pharmacology JID - 0326264 RN - 0 (Acetophenones) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antioxidants) RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Reactive Oxygen Species) RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) RN - 53-59-8 (NADP) RN - B6J7B9UDTR (acetovanillone) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Acetophenones/*pharmacology MH - Anti-Inflammatory Agents/*pharmacology MH - Antioxidants/pharmacology MH - Cells, Cultured MH - Cytokines/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activation MH - Humans MH - Inflammation/enzymology/genetics/immunology/*prevention & control MH - Inflammation Mediators/metabolism MH - Keratinocytes/*drug effects/enzymology/immunology MH - Lipopolysaccharides/pharmacology MH - NADP/metabolism MH - NF-kappa B/*metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*metabolism MH - Time Factors MH - Toll-Like Receptor 4/*antagonists & inhibitors/metabolism OTO - NOTNLM OT - *Akt OT - *Apocynin OT - *Inflammatory mediator production OT - *Keratinocytes OT - *Lipopolysaccharide OT - *Toll-like receptor-4 OT - *mTOR and NF-kappaB pathways EDAT- 2016/09/04 06:00 MHDA- 2017/02/24 06:00 CRDT- 2016/09/04 06:00 PHST- 2016/05/21 00:00 [received] PHST- 2016/08/16 00:00 [accepted] PHST- 2016/09/04 06:00 [pubmed] PHST- 2017/02/24 06:00 [medline] PHST- 2016/09/04 06:00 [entrez] AID - 10.1007/s00210-016-1288-5 [pii] AID - 10.1007/s00210-016-1288-5 [doi] PST - ppublish SO - Naunyn Schmiedebergs Arch Pharmacol. 2016 Dec;389(12):1267-1277. doi: 10.1007/s00210-016-1288-5. Epub 2016 Sep 2.