Involvement of nitric oxide in the induction of interleukin-1 beta in microglia.
In response to in vitro stimulation with lipopolysaccharide (LPS), microglia induce the production of the inflammatory cytokine interleukin-1 beta (IL-1β) together with nitric oxide (NO) and superoxide anion (O2(-)). Here we investigated the role of NO and O2(-) in the signaling mechanism by which IL-1β is induced in microglia. The LPS-inducible IL-1β was significantly suppressed by pretreatment with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, but not by pretreatment with the O2(-) scavenger N-acetyl cysteine, suggesting the close association of NO with IL-1β induction. The pretreatment of microglia with the inducible NO synthase inhibitor 1400W prior to LPS stimulation significantly reduced the production of IL-1β, and the addition of the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) into microglia led to the induction of IL-1β. These results suggested that NO induces IL-1β through a specific signaling cascade. LPS-dependent IL-1β induction was significantly suppressed by inhibitors of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NFκB), indicating that ERK/JNK and NFκB serve in the cascade of IL-1β induction. As expected, ERK/JNK and NFκB were all activated in the SNAP-stimulated microglia. Taken together, these results indicate that NO is an important signaling molecule for the ERK/JNK and NFκB activations, which are requisite to the induction of IL-1β in microglia.
Department of Science and Engineering for Sustainable Innovation, Faculty of Science and Engineering, Soka University, Tokyo 192-8577, Japan.
Kenji
K
Sudo
Department of Science and Engineering for Sustainable Innovation, Faculty of Science and Engineering, Soka University, Tokyo 192-8577, Japan.
Yosuke
Y
Takezawa
National Institute of Neuroscience, Tokyo 187-8502, Japan.
Shinichi
S
Kohsaka
Department of Science and Engineering for Sustainable Innovation, Faculty of Science and Engineering, Soka University, Tokyo 192-8577, Japan. Electronic address: nakajima@t.soka.ac.jp.
Kazuyuki
K
Nakajima
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects; D020932:Nerve Growth Factor / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D020932:Nerve Growth Factor
Interleukin-1β; MAP kinases; Microglia; NFκB; Nitric oxide