Abstract
Various herbal extracts containing luteolin-7-O-glucuronide (L7Gn) have been traditionally used to treat inflammatory diseases. However, systemic studies aimed at elucidating the anti-inflammatory and anti-oxidative mechanisms of L7Gn in macrophages are insufficient. Herein, the anti-inflammatory and anti-oxidative effects of L7Gn and their underlying mechanisms of action in macrophages were explored. L7Gn inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by transcriptional regulation of inducible NO synthase (iNOS) in a dose-dependent manner. The mRNA expression of inflammatory mediators, including cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), was inhibited by L7Gn treatment. This suppression was mediated through transforming growth factor beta-activated kinase 1 (TAK1) inhibition that leads to reduced activation of nuclear factor-κB (NF-κB), p38, and c-Jun N-terminal kinase (JNK). L7Gn also enhanced the radical scavenging effect and increased the expression of anti-oxidative regulators, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1), by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) activation. These results indicate that L7Gn exhibits anti-inflammatory and anti-oxidative properties in LPS-stimulated murine macrophages, suggesting that L7Gn may be a suitable candidate to treat severe inflammation and oxidative stress.
Highlights
Macrophages provide the first line of defense against external pathogens
SpiantchewthaeystrsauncshcraipstNioFn-aκlBin, mhiibtiotgioenn-oafcitNivOaSteids pcaruotseeidnbkyintahseein(MhiAbiPtiKon), aonfdththeemacatjiovratiinofnlaomf mHOat-o1rvyiasitghneaNlinrfg2 ppaatthhwwaayy,sitswuachs hayspNotFh-eκsBiz,edmtihtoagteLn7-Gacntimvaigtehdt pplraoytereinguklaintoarsye r(oMleAsPinKt)h, aensedstihgenaaclitnivgaptiaotnhwofaHysO. -1 via the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathway, it was hypothesized that L7Gn might play reguTlaotoerlyurcoidleasteinatnhtei-siensfliagmnamlinatgopryatheffweacytss. of L7Gn and their underlying mechanism of action, the mTRoNeAluecxidparetessaionnti-lienvfelalsmomf vaatoriroyuesfifneflctasmomf Lat7oGryn manedditahteoirrs,uinndcleurdlyininggcymcelocohxayngisemnaosef-a2c(tCioOnX, t-h2)e, ImL-R1Nβ,AILe-x6p, raensdsioTnNlFev-αe,lsinofLvPaSr-iostuims iunlfaltaemdmRaAtoWry2m64e.d7iamtoarcsr,oipnhclaugdeisngwceyreclomoexaysguerneadse(-F2ig(uCrOeX2-C2))
L7GPSntirnedautmceednmt, wRNheAreeaxspTrNesFs-ioαnmleRvNelAs olefvCeOlsXw-2e,rIeLm-6o, adnedraItLel-y1βrewdeurceecdl.eaFrulyrthreedrmucoerde,btyheL7CGOnXt-r2eaptrmoteenint, ewxhpereressaisoTnNwFa-sαamlsoRiNnhAibleitveedlsinwLePrSe-mstiomduerlaatteedlyRrAedWuc2e6d4..7Fcuerltlsheurpmonorter,eathtme CenOt Xw-i2thpLro7tGeinn(Fexigpurreess2iDon). was inhibited in LPS-stimulated RAW 264.7 cells upon treatment with L7Gn (Figure 2D). These data imply that L7Gn might exert anti-inflammatory effects by the transcriptional regulation of inflammatory-mediator expression in macrophages
Summary
Macrophages provide the first line of defense against external pathogens. One of the most potent pathogens for macrophage activation is bacterial lipopolysaccharide (LPS), the toll-like receptor 4 (TLR4) ligand [1,2]. Upon stimulation by LPS, macrophages release various inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2) [3]. Under normal conditions, these inflammatory mediators protect the human body against infectious diseases. Overproduction of reactive oxygen species (ROS) caused by oxidative stress is implicated in the pathogenesis of several human diseases, including atherosclerosis, cancer, neurodegenerative Excessive inflammatory responses, which result in overproduction of inflammatory mediators, may lead to various inflammatory diseases, such as arthritis, asthma, multiple sclerosis, inflammatory bowel disease, and atherosclerosis [4,5,6].
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