2-aminopurine inhibits lipopolysaccharide-induced nitric oxide production by preventing IFN-beta production.
2-aminopurine (2-AP) is widely used as a specific inhibitor for double stranded-RNA dependent protein kinase (PKR). Here we report that 2-AP can inhibit lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production through the prevention of interferon (IFN)-beta production. 2-AP significantly inhibited NO production in LPS-stimulated RAW 264 murine macrophage cells. 2-AP also reduced the expression of IFN-beta and IFN-inducible genes, such as IFN-gamma-inducible protein (IP)-10 and immune-responsive gene (IRG)-1, and the inducible type of NO synthase (iNOS) mRNA in response to LPS. The addition of exogenous IFN-beta restored 2-AP-inhibited NO production in response to LPS. On the other hand, there was only partial inhibition by 2-AP of nuclear factor (NF)-kappaB activation, IL-6 mRNA expression and tumor necrosis factor (TNF)-alpha production. These results suggested that 2-AP inhibited LPS-induced IFN-beta production by preventing Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling rather than myeloid differentiation factor (MyD) 88-dependent signaling, resulting in the inhibition of NO production.
Sugiyama
Tsuyoshi
T
Department of Microbiology and Immunology, School of Medicine and Research Center for Infectious Disease, Aichi Medical University, Aichi 480-1195, Japan. sugiyama@gifu-pu.ac.jp
Fujita
Megumi
M
Koide
Naoki
N
Mori
Isamu
I
Yoshida
Tomoaki
T
Mori
Hiroshi
H
Yokochi
Takashi
T
D015075:2-Aminopurine / Q000494:pharmacology*; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D004347:Drug Interactions; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D011070:Poly I-C / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D015075:2-Aminopurine; D033942:Adaptor Proteins, Vesicular Transport; D000963:Antimetabolites; D016899:Interferon-beta; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011070:Poly I-C; D012313:RNA; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C496317:Nos2 protein, mouse