The fixed structure of Licochalcone A by alpha, beta-unsaturated ketone is necessary for anti-inflammatory activity through the inhibition of NF-kappaB activation.
Glycyrrhiza inflata has been used as a traditional medicine with anti-inflammatory activity. Previously, we reported that a major component, Licochalcone A, potently inhibited TNFalpha-induced NF-kappaB activation by inhibiting IKKbeta activation. In this study, we investigated whether the fixed structure of Licochalcone A by alpha, beta-unsaturated ketone is required for its inhibitory effect of NF-kappaB activation. Interestingly, reduced Licochalcone A, which lacks a double bond, failed to inhibit TNFalpha-induced NF-kappaB activation. Whereas Licochalcone A potently inhibited TNFalpha-induced IKK activation, IkappaBalpha degradation, nuclear localization of NF-kappaB and its DNA binding activity, no inhibitory effect was observed by reduced Licochalcone A. In addition, TNFalpha-induced expression of inflammatory cytokines, CCL2/MCP-1 and CXCL1/KC, was clearly inhibited by Licochalcone A but not reduced Licochalcone A. As a result, culture media pretreated with Licochalcone A but not reduced Licochalcone A following TNFalpha stimulation significantly inhibited the chemotactic activity of neutrophils. Furthermore, acute carrageenan-induced paw edema in mice was markedly inhibited by administration of Licochalcone A but not reduced Licochalcone A. Taken together, it is suggested that Licochalcone A is a promising anti-inflammatory drug in vivo and its fixed structure is critical for anti-inflammatory activity.
Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. tago-mg@pha.keio.ac.jp
Megumi
M
Funakoshi-Tago
Kei
K
Nakamura
Rina
R
Tsuruya
Masashi
M
Hatanaka
Tadahiko
T
Mashino
Yoshiko
Y
Sonoda
Tadashi
T
Kasahara
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan / Q000008:administration & dosage; D047188:Chalcones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D006035:Glycyrrhiza; D007659:Ketones / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction
D000893:Anti-Inflammatory Agents; D047188:Chalcones; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D007659:Ketones; D016328:NF-kappa B; D002351:Carrageenan; C070840:licochalcone A