The Orphan Nuclear Receptor NR4A3 Is Involved in the Function of Dendritic Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

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-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 IKKβ, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced bone marrow–derived DCs. The knockdown experiments using siRNAs for IKKβ, IRF4, and/or IRF8 indicated that LPS-induced upregulation of IL-10 and IL-6 was reduced in IKKβ 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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