LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells.
The current study examined the potential involvement of phosphatidylinositol 3 phosphate kinase (PI3K) in interferon-gamma (IFN-gamma)-stimulated nitric oxide (NO) generation in BV2 murine microglial cells. We found that LY294002, a PI3K inhibitor, markedly reduced IFN-gamma-induced morphological changes, NO production, and cell death. The inhibitory effect of LY294002 on NO generation may be mediated through specific inhibition of signal transducer and activator-1 (STAT1) and NF-kappaB, which are activated by IFN-gamma. Induction of the mRNA for IFN-gamma-mediated interferon response factor (IRF-1) and inducible protein-10 (IP-10) was not significantly affected by LY294002, indicating that suppression of PI3K may not be sufficient for downregulation of these genes. Although it remains unclear how PI3K signaling is involved in IFN-gamma-mediated inflammatory reactions in the brain, our findings provide some insight into the inflammatory mechanisms of IFN-gamma in the brain and suggest that regulators of the PI3K pathway may act as anti-inflammatory agents in microglia.
Hwang
So-Young
SY
Research Institute, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
Jung
Jae-Seob
JS
Lim
Soo-Jeong
SJ
Kim
Joo-Young
JY
Kim
Tae-Hyun
TH
Cho
Kwan-Ho
KH
Han
Inn-Oc
IO
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D051058:Oncogene Protein v-akt; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015682:Retroviridae Proteins, Oncogenic; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014443:Tyrosine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; D051058:Oncogene Protein v-akt