NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein.

• 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-kappaB (NF-kappaB) activation and blocking of NF-kappaB 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-kappaB-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-kappaB 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-kappaB system.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Analysis of Variance

Animals

Blotting

Western

Brain-Derived Neurotrophic Factor

genetics

metabolism

Cells

Cultured

Gene Silencing

Hippocampus

cytology

metabolism

Interleukin-6

metabolism

Mice

Mice

Transgenic

NF-kappa B

metabolism

Nerve Net

metabolism

Neurons

metabolism

Oligonucleotide Array Sequence Analysis

RNA

Messenger

metabolism

RNA

Small Interfering

metabolism

Rats

Receptor

trkB

metabolism

Reverse Transcriptase Polymerase Chain Reaction

Transfection

Up-Regulation

X-Linked Inhibitor of Apoptosis Protein

genetics

metabolism

brain-derived neurotrophic factor

MEDICINE

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)