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NF‐κB‐dependent regulation of brain‐derived neurotrophic factor in hippocampal neurons by X‐linked inhibitor of apoptosis protein
Author(s) -
Kairisalo Minna,
Korhonen Laura,
Sepp Mari,
Pruunsild Priit,
Kukkonen Jyrki P.,
Kivinen Jenny,
Timmusk Tõnis,
Blomgren Klas,
Lindholm Dan
Publication year - 2009
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2009.06898.x
Subject(s) - xiap , tropomyosin receptor kinase b , neurotrophic factors , inhibitor of apoptosis , chemistry , brain derived neurotrophic factor , microbiology and biotechnology , downregulation and upregulation , hippocampal formation , biology , apoptosis , endocrinology , receptor , programmed cell death , caspase , biochemistry , gene
Abstract X chromosome‐linked inhibitor of apoptosis protein (XIAP) is an anti‐apoptotic protein enhancing cell survival. Brain‐derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element‐binding protein. The mechanism involved nuclear factor‐κB (NF‐κB) activation and blocking of NF‐κB signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)‐6, which is an NF‐κB‐responsive gene. The addition of IL‐6 elevated whereas incubation with IL‐6‐blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF‐κB in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL‐6 and XIAP interconnected via the NF‐κB system.