Gamma-aminobutyric acid inhibits synergistic interleukin-6 release but not transcriptional activation in astrocytoma cells.
OBJECTIVE
A decline in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may enhance cytokine release in Alzheimer's disease (AD) resulting in neuroinflammation. We investigated the GABA-mediated suppression of the synergistic release of interleukin (IL)-6 due to interleukin 1-beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha).


METHODS
Rat C6 astrocytoma cells were treated with IL-1 beta and TNF-alpha in the absence and presence of GABA. Activation of p38, degradation of I kappaB-alpha and total cellular IL-6 were determined by Western blot analysis. IL-6 release and gene expression were measured by ELISA and RT-PCR, respectively.


RESULTS
Although p38 and nuclear factor (NF)-kappaB are essential for the synergistic release of IL-6, GABA did not affect either p38 phosphorylation or I kappaB-alpha degradation. Additionally, GABA suppressed IL-6 release but did not alter cytokine-driven synergistic increases in IL-6 gene expression. Western blot analysis revealed that co-treatments with IL-1 beta and TNF-alpha resulted in an increase in intracellular IL-6 that was prevented by GABA.


CONCLUSIONS
GABA-induced inhibition of IL-6 release appears to coincide with a reduction in cellular IL-6. The GABA-induced suppression of IL-6 release may include inhibition of IL-6 gene translation.
Roach
Joseph D
JD
Department of Chemistry, University of Nevada, Las Vegas, Nevada 89154-4003, USA.
Aguinaldo
Grant T
GT
Jonnalagadda
Kaumudi
K
Hughes
Francis M
FM
Spangelo
Bryan L
BL
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001254:Astrocytoma / Q000235:genetics* / Q000276:immunology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D005680:gamma-Aminobutyric Acid; D048051:p38 Mitogen-Activated Protein Kinases