title: Microglia-derived proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta induce Purkinje neuronal apoptosis via their receptors in hypoxic neonatal rat brain.
abstract: The developing cerebellum is extremely vulnerable to hypoxia which can damage the Purkinje neurons. We hypothesized that this might be mediated by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) derived from activated microglia as in other brain areas. One-day-old rats were subjected to hypoxia following, which the expression changes of various proteins in the cerebellum including hypoxia inducible factor-1α, TNF-α, IL-1β, TNF-R1 and IL-1R1 were analyzed. Following hypoxic exposure, TNF-α and IL-1β immunoexpression in microglia was enhanced coupled by that of TNF-R1 and IL-1R1 in the Purkinje neurons. Along with this, hypoxic microglia in vitro showed enhanced release of TNF-α and IL-1β whose receptor expression was concomitantly increased in the Purkinje neurons. In addition, nitric oxide (NO) level was significantly increased in the cerebellum and cultured microglia subjected to hypoxic exposure. Moreover, cultured Purkinje neurons treated with conditioned medium derived from hypoxic microglia underwent apoptosis but the incidence was significantly reduced when the cells were treated with the same medium that was neutralized with TNF-α/IL-1β antibody. We conclude that hypoxic microglia in the neonatal cerebellum produce increased amounts of NO, TNF-α and IL-1β which when acting via their respective receptors could induce Purkinje neuron death.
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, 117597, Singapore, antkaurc@nus.edu.sg.
authors.forename: Charanjit
authors.initials: C
authors.lastname: Kaur
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Sivakumar
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zou
authors.forename: Eng-Ang
authors.initials: EA
authors.lastname: Ling
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D039481:CD11b Antigen / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D002534:Hypoxia, Brain / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D037102:Lectins; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018121:Receptors, Cytokine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D037102:Lectins; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide