O-methylated flavonol isorhamnetin prevents acute inflammation through blocking of NF-κB activation

• Published in: Food and chemical toxicology Vol. 59; pp. 362 - 372
• Main Authors: Yang, Ji Hye, Kim, Sang Chan, Shin, Bo Yeon, Jin, So Hee, Jo, Mi Jeong, Jegal, Kyung Hwan, Kim, Young Woo, Lee, Jong Rok, Ku, Sae Kwang, Cho, Il Je, Ki, Sung Hwan
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2013; Elsevier
• Subjects: Animals; Anti-inflammation; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - isolation & purification; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; carrageenan; Cell Line, Transformed; Cell Nucleus - drug effects; Cell Nucleus - immunology; Cell Nucleus - metabolism; Cell Nucleus - pathology; Disease Models, Animal; Edema - immunology; Edema - metabolism; Edema - pathology; Edema - prevention & control; Ethnopharmacology; gene expression; gene induction; genes; IKK; inducible nitric oxide synthase; inflammation; interleukin-1beta; interleukin-6; Isorhamnetin; JNK; lipopolysaccharides; luciferase; Lymphocyte Activation - drug effects; Macrophage Activation - drug effects; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical sciences; Medicine, East Asian Traditional; Mice; mitogen-activated protein kinase; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; nitric oxide; Nuclear factor-kappa B (NF-κB); Oenanthe - chemistry; Oenanthe javanica; phosphorylation; Protein Transport - drug effects; Quercetin - analogs & derivatives; Quercetin - chemistry; Quercetin - isolation & purification; Quercetin - pharmacology; Quercetin - therapeutic use; Random Allocation; Rats; Rats, Sprague-Dawley; Republic of Korea; Skin - drug effects; Skin - immunology; Skin - metabolism; Skin - pathology; Toxicology; transcription factor NF-kappa B; tumor necrosis factor-alpha; NO; IL; H&E; JNK; IKK; MAPK; AP-1; TNF; MPO; LPS; Anti-inflammation; IκB; NF-κB; Isorhamnetin; NOS; PI3K; Nuclear factor-kappa B (NF-κB); TLR; Prevention; Acute; Blocking; Activation; Inflammation; Transcription factor NFκB; Methylation; Hematoxylin & Eosin; IκB kinase; mitogen-activated protein kinase; nitric oxide synthase; interleukin; phosphatidylinositol 3-kinase; nitric oxide; nuclear factor-kappa B; activating protein-1; myeloperoxidase; tumor necrosis factor; inhibitory κB; toll-like receptor; lipopolysaccharide
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.05.049

[Display omitted] •We investigated the anti-inflammatory effect of isorhamnetin in vivo and in vitro.•Isorhamnetin inhibited the swelling volume and the thickness of hind paws.•Isorhamnetin inhibited pro-inflammatory genes expression in LPS-stimulated cells via NF-κB inactivation.•Moreover, isorhamnetin inhibited LPS-induced JNK, AKT/IKKα/β phosphorylation. Here, we isolated isorhamnetin, a natural 3′-O-methylated flavonoid, from water dropwort (Oenanthe javanica, Umbelliferae) and investigated its ability to protect against acute inflammation in vivo and in vitro. To induce paw swelling, the hind paw of each rat was injected with a carrageenan 1h after vehicle or isorhamnetin treatment. In vitro effect and mechanism studies were performed in lipopolysaccharide (LPS)-activated macrophages. Administration of isorhamnetin markedly inhibited the swelling volume and the thickness of hind paws. Moreover, isorhamnetin significantly reduced inflammatory cell infiltration and pro-inflammatory gene expression in rats. Isorhamnetin pretreatment inhibited inducible nitric oxide synthase (iNOS) expression and NO release in LPS-stimulated cells. Activation of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) is the key step in the iNOS gene induction. Isorhamnetin specifically inhibited NF-κB luciferase activity, but not AP-1. Pretreatment with isorhamnetin suppressed NF-κB nuclear translocation in accordance with decreased phosphorylation and degradation of inhibitory-κB. Consistently, TNF-α, IL-1β and IL-6 expression, representative NF-κB target genes, were almost completely prohibited by isorhamnetin. Furthermore, isorhamnetin inhibited LPS-induced JNK and AKT/IKKα/β phosphorylation. Our results suggest that isorhamnetin inhibited JNK, and AKT/IKKα/β activation, leading to NF-κB inactivation, which might contribute to the inhibition of the acute inflammatory response.