title: Inhibition of 12/15-lipoxygenase by baicalein induces microglia PPARβ/δ: a potential therapeutic role for CNS autoimmune disease.
abstract: 12/15-Lipoxygenase (12/15-LO) is an enzyme that converts polyunsaturated fatty acids into bioactive lipid derivatives. In this study, we showed that inhibition of 12/15-LO by baicalein (BA) significantly attenuated clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Inhibited migration of autoimmune T cells into the central nervous system (CNS) by BA treatment could be attributed to reduced activation of microglia, which was indicated by suppressed phagocytosis, and decreased production of proinflammatory cytokines and chemokines in the CNS. We further observed that inhibition of 12/15-LO with BA led to increased expression of peroxisome proliferator-activated receptor (PPAR)β/δ in microglia of EAE mice. This was confirmed in vitro in primary microglia and a microglia cell line, BV2. In addition, we demonstrated that BA did not affect 12/15-LO or 5-lipoxygenase (5-LO) expression in microglia, but significantly decreased 12/15-LO products without influencing the levels of 5-LO metabolites. Moreover, among these compounds only 12/15-LO metabolite 12-hydroxyeicosatetraenoic acid was able to reverse BA-mediated upregulation of PPARβ/δ in BV2 cells. We also showed that inhibition of microglia activation by PPARβ/δ was associated with repressed NF-κB and MAPK activities. Our findings indicate that inhibition of 12/15-LO induces PPARβ/δ, demonstrating important regulatory properties of 12/15-LO in CNS inflammation. This reveals potential therapeutic applications for MS.
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Dang
authors.forename: M
authors.initials: M
authors.lastname: Jin
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: B
authors.initials: B
authors.lastname: Wan
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes
chemical_list: C475064:12-15-lipoxygenase; D004791:Enzyme Inhibitors; D044950:Flavanones; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D020928:Mitogen-Activated Protein Kinases
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