BACKGROUND: Luteolin, a plant derived flavonoid, exerts a variety of 
pharmacological activities and anti-oxidant properties associated with its 
capacity to scavenge oxygen and nitrogen species. Luteolin also shows potent 
anti-inflammatory activities by inhibiting nuclear factor kappa B (NFkB) 
signaling in immune cells. To better understand the immuno-modulatory effects of 
this important flavonoid, we performed a genome-wide expression analysis in 
pro-inflammatory challenged microglia treated with luteolin and conducted a 
phenotypic and functional characterization.
METHODS: Resting and LPS-activated BV-2 microglia were treated with luteolin in 
various concentrations and mRNA levels of pro-inflammatory markers were 
determined. DNA microarray experiments and bioinformatic data mining were 
performed to capture global transcriptomic changes following luteolin 
stimulation of microglia. Extensive qRT-PCR analyses were carried out for an 
independent confirmation of newly identified luteolin-regulated transcripts. The 
activation state of luteolin-treated microglia was assessed by morphological 
characterization. Microglia-mediated neurotoxicity was assessed by quantifying 
secreted nitric oxide levels and apoptosis of 661W photoreceptors cultured in 
microglia-conditioned medium.
RESULTS: Luteolin dose-dependently suppressed pro-inflammatory marker expression 
in LPS-activated microglia and triggered global changes in the microglial 
transcriptome with more than 50 differentially expressed transcripts. 
Pro-inflammatory and pro-apoptotic gene expression was effectively blocked by 
luteolin. In contrast, mRNA levels of genes related to anti-oxidant metabolism, 
phagocytic uptake, ramification, and chemotaxis were significantly induced. 
Luteolin treatment had a major effect on microglial morphology leading to 
ramification of formerly amoeboid cells associated with the formation of long 
filopodia. When co-incubated with luteolin, LPS-activated microglia showed 
strongly reduced NO secretion and significantly decreased neurotoxicity on 661W 
photoreceptor cultures.
CONCLUSIONS: Our findings confirm the inhibitory effects of luteolin on 
pro-inflammatory cytokine expression in microglia. Moreover, our transcriptomic 
data suggest that this flavonoid is a potent modulator of microglial activation 
and affects several signaling pathways leading to a unique phenotype with 
anti-inflammatory, anti-oxidative, and neuroprotective characteristics. With the 
identification of several novel luteolin-regulated genes, our findings provide a 
molecular basis to understand the versatile effects of luteolin on microglial 
homeostasis. The data also suggest that luteolin could be a promising candidate 
to develop immuno-modulatory and neuroprotective therapies for the treatment of 
neurodegenerative disorders.