title: Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia.
abstract: The release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and iNOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 microM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-alpha and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules.
authors.affiliation: Department of Anatomy, Molecular Neurobiology Laboratory, Faculty of Medicine, National University of Singapore, Singapore. antstd@nus.edu.sg
authors.forename: S Thameem
authors.initials: ST
authors.lastname: Dheen
authors.forename: Yan
authors.initials: Y
authors.lastname: Jun
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yan
authors.forename: Samuel S W
authors.initials: SS
authors.lastname: Tay
authors.forename: Eng Ang
authors.initials: EA
authors.lastname: Ling
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D018836:Inflammation Mediators / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; D009573:Nitrites; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014409:Tumor Necrosis Factor-alpha; C082925:retinoic acid receptor beta; D009569:Nitric Oxide; D014212:Tretinoin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat