Anti-Inflammatory Effects of Magnolol and Honokiol are Mediated through Inhibition of the Downstream Pathway of MEKK-1 in NF-κB Activation Signaling

Abstract

Propionibacterium acnes, an anaerobic pathogen, plays an important role in the pathogenesis of acne and seems to initiate the inflammatory process by producing proinflammatory cytokines. In order to demonstrate the anti-inflammatory effects and action mechanisms of magnolol and honokiol, several methods were employed. Through DPPH and SOD activity assays, we found that although both magnolol and honokiol have antioxidant activities, honokiol has relatively stronger antioxidant activities than magnolol {[for DPPH assay, % of DPPH bleaching of magnolol and honokiol (500 microM magnolol: 19.8%; 500 microM honokiol: 67.3%)]; [for SOD assay, SOD activity (200 microM magnolol: 53.4%; 200 microM honokiol: 64.3%)]}. Moreover, the production of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) induced by P. acnes in THP-1 cells, a human monocytic cell line, was reduced by magnolol and honokiol {[for IL-8 (10 microM magnolol: 42.7% inhibition; 10 microM honokiol: 51.4% inhibition)]; [for TNF-alpha (10 microM magnolol: 20.3% inhibition; 10 microM honokiol: 39.0% inhibition)]}. Cyclooxygenase-2 (Cox-2) activity was also suppressed by them [(15 microM magnolol: 45.8% inhibition), (15 microM honokiol: 66.3% inhibition)]. Using a nuclear factor-kappaB (NF-kappaB) luciferase reporter assay system and Western analysis, we identified that magnolol and honokiol exert their anti-inflammatory effects by inhibiting the NF-kappaB element, which exists in Cox-2, IL-8, and TNF-alpha promoters [(15 microM magnolol: 44.8% inhibition), (15 microM honokiol: 42.3% inhibition)]. Of particular note is that magnolol and honokiol operate downstream of the MEKK-1 molecule. Together with their previously known antibacterial activity against P. acnes and based on these results, we suggest that magnolol and honokiol may be introduced as possible acne-mitigating agents.

Honokiol Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion through Modulation of Nuclear Factor-κB Activation Pathway

“…Honokiol also inhibited the TNFinduced COX-2 promoter activity, which is regulated by NF-nB (30). These results agree with a recent report (5) showing that honokiol inhibits NF-nB luciferase reporter activity. We also found that honokiol suppressed NF-nB activation induced by overexpression of TNFR1, TRADD, TRAF2, NIK, and IKK plasmids but had no effect on activation induced by p65 plasmid.…”

“…The suppression of invasion (32) and angiogenesis (33) reported previously agrees with the results reported here. The inflammatory cytokines TNF and interleukin-8, both known to promote angiogenesis, have also been shown to be down-regulated by honokiol (4,5). The down-regulation of nitric oxide synthesis by honokiol reported previously (4) also likely occurs through the suppression of NF-nB activation as reported here.…”

“…Extensive research has shown that honokiol inhibits skin tumor promotion (3), inhibits nitric oxide synthesis and tumor necrosis factor (TNF) expression (4,5), inhibits invasion (6), down-regulates antiapoptotic protein Bcl-x L (7), inhibits angiogenesis and tumor growth in vivo (8), induces caspasedependent apoptosis in B-cell chronic lymphocytic leukemia cells through down-regulation of the antiapoptotic protein Mcl-1 (9), and overcomes drug resistance in multiple myeloma (10). Exactly how honokiol mediates all these effects is poorly understood.…”

Cytoprotective Effects of KIOM-79 on Streptozotocin Induced Cell Damage by Inhibiting ERK and AP-1

“…Magnolia officinalis reportedly has antimutagenic, 8) hepatocytic protective, 9,10) neuroprotective, 11) and anti-inflammatory effects. 12) Pueraria lobata reportedly has antimutagenic, antidiabetic and antioxidant effects. [13][14][15] Glycyrrhiza uralensis has detoxification, antiulcer, antiinflammation, antiviral, antiatherogenic, and anticarcinogenic effects, 16) and Euphorbia pekinensis has for antiviral and cytotoxic activities.…”

Honokiol Potentiates Pentobarbital-Induced Sleeping Behaviors through GABAAReceptor Cl-Channel Activation

“…The biphenolic compounds were initially thought of as the major active compounds of the plants. Honokiol has several pharmacological benefits, including antimicrobial (Clark et al, 1981), anti-inflammatory (Liou et al, 2003a;Lee et al, 2005;Chiang et al, 2006), antioxidative (Liou et al, 2003b;Sheu et al, 2008), anxiolytic (Kuribara et al, 1998;Kuribara et al, 2000), antiangiogenic (Liou et al, 2003c;Li et al, 2008), and antineoplastic effects (Battle et al, 2005;Sheu et al, 2007).…”