title: The anti-inflammatory effect of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol by targeting Lyn kinase in human neutrophils.
abstract: The undesirable respiratory burst in neutrophils can lead to inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol (honokiol), a lignan extracted from the stem bark of Magnolia officinalis Rehd. et Wils (Magnoliaceae), on N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced respiratory burst in human neutrophils. Signaling pathways regulated by honokiol which modulate fMLP-induced respiratory burst and cathepsin G release were evaluated by phosphorylation of Src family kinase induced by fMLP, Src family kinases activities and by immunoblotting analysis of the downstream targets of Src kinase. Briefly, honokiol inhibited fMLP-induced superoxide anion production (IC50 = 9.80 ± 0.21 μM, n = 4), cathepsin G release (IC50 = 14.23 ± 1.43 μM, n = 4) and migration (IC50 = 5.69 ± 1.51 μM, n = 4) in a concentration dependent manner. Further, honokiol specifically suppresses fMLP-induced Lyn (a member of the Src kinase family) phosphorylation, by inhibiting Lyn kinase activity. Consequently, honokiol attenuated the downstream targets of Lyn kinase, such as Tec translocation from the cytosol to the inner leaflet of the plasma membrane, phosphorylation of AKT, P38, PLCγ2, protein kinase C and membrane localization of p47(phox). On the other hand, fMLP-induced phosphorylation of Hck, Fgr kinase activity (other members of Src kinase), downstream phosphorylation of Vav1 and extracellular signal-regulated kinase remained unaffected. In addition, honokiol neither inhibited NADPH oxidase activity nor increased cyclic AMP levels. Honokiol is not a competitive or allosteric antagonist of fMLP. In conclusion, honokiol specifically modulates fMLP-mediated neutrophil activation by inhibiting Lyn activation which subsequently interferes with the activation of PLCγ2, AKT, p38, protein kinase C, and p47(phox).
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan. Electronic address: liaoch@mail.cgu.edu.tw.
authors.forename: Hsiang-Ruei
authors.initials: HR
authors.lastname: Liao
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Ching-Ru
authors.initials: CR
authors.lastname: Chien
authors.affiliation: Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Ta-jen University, Taiwan.
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Traditional Chinese Medicine, College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Tzung-Yan
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Shinn-Zhi
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D056649:Cathepsin G / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D055815:Young Adult; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D002118:Calcium; D056649:Cathepsin G; D000242:Cyclic AMP; D017705:Lignans; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; D051966:Phospholipase C gamma; D051057:Proto-Oncogene Proteins c-akt; D044042:Receptors, Formyl Peptide; D013481:Superoxides; D019061:src-Family Kinases; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C060505:neutrophil cytosolic factor 1; C060902:lyn protein-tyrosine kinase; C534094:CTSG protein, human
keywords: Honokiol; Lyn; Neutrophil; Src; fMLP