Journal
JOURNAL OF IMMUNOLOGY
Volume 199, Issue 8, Pages 2958-2967Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1601911
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Funding
- Funding Program for Next Generation World-Leading Researchers through Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) Grant [LS111]
- MEXT-Supported Program for Strategic Research Foundation at Private Universities (Translational Research Center, Tokyo University of Science)
- Tokyo Biochemical Research Foundation
- Japanese Society for Promotion of Science for Young Scientists [10792, 3241]
- Tokyo University of Science
- Grants-in-Aid for Scientific Research [17K15276, 16J03241] Funding Source: KAKEN
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NR4A3/NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3 in gene expression of dendritic cells (DCs), we introduced NR4A3 small interfering RNA ( siRNA) into bone marrow-derived DCs and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NF-kappa B signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly upregulated by TLR-mediated stimulation in DCs. NR4A3 knockdown significantly suppressed LPS, CpG, or poly(I:C)mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12. Proliferation and IL-2 production levels of T cells cocultured with NR4A3 knocked-down DCs were significantly lower than that of T cells cocultured with control DCs. Furthermore, the expression of IKK beta, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced bone marrow-derived DCs. The knockdown experiments using siRNAs for IKK beta, IRF4, and/or IRF8 indicated that LPS-induced upregulation of IL-10 and IL-6 was reduced in IKKb knocked-down cells, and that the upregulation of IL-12 was suppressed by the knockdown of IRF4 and IRF8. Taken together, these results indicate that NR4A3 is involved in TLR-mediated activation and gene expression of DCs.
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