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 μM magnolol: 19.8 %; 500 μM honokiol: 67.3 %)]; [for SOD assay, SOD activity (200 μM magnolol: 53.4 %; 200 μM honokiol: 64.3 %)]}. Moreover, the production of interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) induced by P. acnes in THP-1 cells, a human monocytic cell line, was reduced by magnolol and honokiol {[for IL-8 (10 μM magnolol: 42.7 % inhibition; 10 μM honokiol: 51.4 % inhibition)]; [for TNF-α (10 μM magnolol: 20.3 % inhibition; 10 μM honokiol: 39.0 % inhibition)]}. Cyclooxygenase-2 (Cox-2) activity was also suppressed by them [(15 μM magnolol: 45.8 % inhibition), (15 μM honokiol: 66.3 % inhibition)]. Using a nuclear factor-κB (NF-κB) luciferase reporter assay system and Western analysis, we identified that magnolol and honokiol exert their anti-inflammatory effects by inhibiting the NF-κB element, which exists in Cox-2, IL-8, and TNF-α promoters [(15 μM magnolol: 44.8 % inhibition), (15 μM 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.

Abbreviations

IL:interleukin

LPS:lipopolysaccharide

TNF-α:tumor necrosis factor-α

NF-κB:nuclear factor-κB

Key words

Magnolol - honokiol - nuclear transcription factor-κB - MEKK-1 - anti-inflammatory effect

References

• 1 Yuji M, Hisashi K, Makoto M, Mitsutoshi Y, Susan T W. Identification of magnolol and honokiol as anxiolytic agents in extracts of Saiboku-to, an Oriental herbal medicine.  J Nat Prod. 1998;  61 135-38
• 2 Marzulli F N, Maibach H I. Dermatotoxicity. 4th edition Hemisphere Publishing Corporation Ney York; 1991
• 3 Guin J, Huber D, Gielerak P. Antibiotic sensitivity of comedonal Propionibacterium acnes .  Acta Derm Venereol. 1979;  59 552-4
• 4 Shin T Y, Kim D K, Chae B S, Lee E J. Antiallergic action of Magnolia officinalis on immediate hypersensitivity reaction.  Arch Pharm Res. 2001;  24 249-55
• 5 Ikeda K, Nagase H. Magnolol has the ability to induce apoptosis in tumor cells.  Biol Pharm Bull. 2002;  25 1546-9
• 6 Bang K H, Kim Y K, Min B S, Na M K, Rhee Y H, Lee J P, Bae K H. Antifungal activity of magnolol and honokiol.  Arch Pharm Res. 2000;  23 46-9
• 7 Chang B, Lee Y, Ku Y, Bae K, Chung C. Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms.  Planta Medica. 1998;  64 367-9
• 8 Clark A, El-Feraly F, Li W. Antimicrobial activity of phenolic constituents of Magnolia grandiflora .  J Pharm Sci. 1981;  70 951-2
• 9 Ho K Y, Tsai C C, Chen C P, Huang J S, Lin C C. Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis .  Phytother Res. 2001;  15 39-41
• 10 Junho P, Jongsung L, Eunsun J, Yumi P, Kukhyun K, Byunghwa P, Kwangseon J, Eunkyung P, Jieun K, Deokhoon P. In vitro antibacterial activity and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp.  Eur J Pharm. 2004;  496 189-95
• 11 Vowels B R, Yang S, Leyden J J. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: Implications for chronic inflammatory acne.  Infect Immunity. 1995;  63 3158-65
• 12 Lo Y C, Teng C M, Chen C F, Chen C C, Hong C Y. Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation.  Biochem Pharmacol. 1994;  47 549-53
• 13 Wang Y, Li C -Y, Lin I -H, Lee A -R, Hu M -K. Synthesis and radical scavenging of novel magnolol derivatives.  J Pharm Pharmacol. 2002;  54 1697-703
• 14 Smith C J, Zhang Y, Kobolt C M. Pharmacological analysis of cyclooxygenase-1 in inflammation.  Proc Natl Acad Sci USA. 1998;  95 13 313-8
• 15 Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences.  Cell. 1986;  46 705-16
• 16 Joel L P, David B. Two pathways to NF-κB.  Mol Cell. 2002;  10 693-701
• 17 Unna P. The histopathology of disease of the skin. Macmillan & Co New York; 1986
• 18 Strauss J S, Kligman A M. The pathologic dynamics of acne vulgaris.  Acta Dermatol. 1960;  82 779-91
• 19 Cummins C S, Johnson J L. Corynebacterium parvum: a synonym for Propionibacterium acnes? .  J Gen Microbiol. 1974;  80 433-42
• 20 Morgan M, Thorburn J, Pandolfi P P, Thorburn A. Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms.  J Cell Biol. 2002;  157 975-84
• 21 Krappmann D, Hatada E N, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle P A, Scheidereit C. The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.  J Biol Chem. 2000;  275 29 779-87