Journal
IMMUNOBIOLOGY
Volume 220, Issue 1, Pages 136-141Publisher
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2014.08.010
Keywords
Lipopolysaccharide; MDM2; NF-kappa B; Nutlin-3; P53
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology in Japan (MEXT)
- Strategic Research Foundation Grant-aided Project for Private Universities from MEXT [S1101027]
- Grants-in-Aid for Scientific Research [25460551] Funding Source: KAKEN
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The effect of lipopolysaccharide (LPS) on the expression of p53 protein in RAW 264.7 macrophage cells was examined. LPS downregulated the expression of p53 protein 4-24 h after the stimulation. LPS-induced p53 inhibition was restored with pharmacological inhibitors of c-jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K). It was also restored by inhibitors of MDM2 activation and proteasome. LPS-induced p53 inhibition corresponded to activation of MDM2. LPS-induced MDM2 activation was prevented by inhibitors of JNK and PI3K. The expression of p65 NF-kappa B at a late stage after LPS stimulation was downregulated in the presence of a MDM2 inhibitor. Nutlin-3 as a MDM2 inhibitor reduced LPS-induced production of nitric oxide but not tumor necrosis factor-alpha. Administration of LPS into mice downregulated the in vivo expression of p53 in the livers. Taken together, LPS was suggested to downregulate the expression of p53 via activation of MDM2 and enhance the activation of NF-kappa B at a late stage. (C) 2014 Elsevier GmbH. All rights reserved.
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