Nonparticipation of nuclear factor kappa B (NFkappaB) in the signaling cascade of c-Jun N-terminal kinase (JNK)- and p38 mitogen-activated protein kinase (p38MAPK)-dependent tumor necrosis factor alpha (TNFalpha) induction in lipopolysaccharide (LPS)-stimulated microglia.
The molecular mechanism of cytotoxic cytokine tumor necrosis factor alpha (TNFalpha) induction in microglia remains to be clarified. We have previously reported that p38 mitogen-activated protein kinase (p38MAPK) is an important signaling molecule for the induction of TNFalpha in lipopolysaccharide (LPS)-stimulated microglia. Recently, we have shown that c-Jun N-terminal kinase (JNK) is associated with the induction of TNFalpha. Furthermore, using an NFkappaB inhibitor (SN50), we discovered that activation of nuclear factor kappaB (NFkappaB) may also be linked to TNFalpha induction. We therefore examined the relationship between NFkappaB and the two MAPKs (p38MAPK and JNK) in the signaling cascade of TNFalpha induction in LPS-stimulated microglia. NFkappaB inhibitor SN50 decreased the induction of TNFalpha under the suppressed NFkappaB activation. However, SN50 was found to prevent the activation of MKK3/6-p38MAPK and MKK4-JNK pathways. On the other hand, the other NFkappaB inhibitor ammonium pyrrolidine dithiocarbamate (APDC) neither prevented the activation of p38MAPK and JNK nor inhibited TNFalpha induction in LPS-stimulated microglia, although it was confirmed to serve as an NFkappaB inhibitor. These results suggest that both MKK3/6-p38MAPK and MKK4-JNK pathways are important signaling cascades leading to the induction of TNFalpha in LPS-stimulated microglia, but that NFkappaB itself is not required for this induction.
Uesugi
Miyuki
M
Neurobiology Lab, Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan.
Nakajima
Kazuyuki
K
Tohyama
Yoko
Y
Kohsaka
Shinichi
S
Kurihara
Tadashi
T
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase