Anti-inflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production.
OBJECTIVE
Glycyrrhizae radix has been widely used as a cytoprotective, plant-derived medicine. We have identified a flavanoid, liquiritigenin, as an active component in extracts of Glycyrrhizae radix. This research investigated the effects of liquiritigenin on the induction of inducible NOS (iNOS) and proinflammatory cytokines by lipopolysaccharide (LPS) in Raw264.7 cells, and on paw oedema in rats.


METHODS
iNOS expression was determined by western blotting, real-time reverse transcription-PCR and reporter gene analyses. Tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 were assayed by ELISA. Gel shift assay and immunoblotting were used to assess NF-kappaB activation. The effect of liquiritigenin on acute inflammation in vivo was evaluated using carrageenan-induced paw oedema.


RESULTS
Treatment of Raw264.7 cells with liquiritigenin caused inhibition of LPS-induced NF-kappaB DNA binding activity, due to repression of I-kappaBalpha phosphorylation and degradation. Liquiritigenin treatment prevented LPS from increasing the levels of iNOS protein and mRNA in a concentration-dependent manner. Liquiritigenin also suppressed the production of TNF-alpha, IL-1beta and IL-6 from Raw264.7 cells after LPS. In rats, liquiritigenin treatment inhibited formation of paw oedema induced by carrageenan.


CONCLUSIONS
These results demonstrate that liquiritigenin exerts anti-inflammatory effects, which results from the inhibition of NF-kappaB activation in macrophages, thereby decreasing production of iNOS and proinflammatory cytokines. Our findings showing inhibition by liquiritigenin of paw oedema as well as inflammatory gene induction will help to understand the pharmacology and mode of action of liquiritigenin, and of the anti-inflammatory use of Glycyrrhizae radix.
Kim
Y W
YW
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Zhao
R J
RJ
Park
S J
SJ
Lee
J R
JR
Cho
I J
IJ
Yang
C H
CH
Kim
S G
SG
Kim
S C
SC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015153:Blotting, Western; D002351:Carrageenan; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003720:Densitometry; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D044950:Flavanones / Q000627:therapeutic use*; D019695:Glycyrrhizic Acid / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000096:biosynthesis; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D044950:Flavanones; D000960:Hypolipidemic Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D009573:Nitrites; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D019695:Glycyrrhizic Acid; D002351:Carrageenan; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II; C022616:thiazolyl blue; C083152:liquiritigenin