Lipopolysaccharide-induced transcriptional activation of interleukin-10 is mediated by MAPK- and NF-κB-induced CCAAT/enhancer-binding protein δ in mouse macrophages

We have previously revealed that LPS can activate transcription of the IL-10 gene promoter through transcription factors Sp1, C/EBPP and C/EBP delta in mouse macrophages. In this study, we determined that NF-kappa B and MATK signal pathways, including ERK, JNK, and p38, were all involved in LPS-induced IL-10 gene expression. Treatment of cells with the pharmacological inhibitors of ERK, JNK, p38 and NF-kappa B respectively inhibited LPS-induced IL-10 protein expression in a dose-dependent manner. These inhibitors also decreased the LPS-induced IL-10 mRNA expression at a high concentration used. With transient overexpression of the I kappa B expression plasmids, or the dominant negative plasmids of ERK2, JNK, p38 together with reporter vector containing IL-10 promoter region, all four expression plasmids inhibited LPS-induced IL-10 promoter activity individually. It is known that the increase in protein and DNA binding of C/EBP beta and delta could activate IL-10 gene expression. In this study, we also identified that all four pharmacological inhibitors inhibited the protein expression of C/EBP delta individually, but not C/EBP beta. In the presence of all three MAPK inhibitors, or only NF-kappa B inhibitor, LPS-induced protein expression and DNA binding of C/EBP delta were completely inhibited simultaneously, and LPS-induced expression of IL-10 protein and mRNA was also inhibited totally. Taken together, these results suggested that LPS-induced IL-10 expression was mediated at least through the pathway of NF-kappa B- and MAPK-induced protein expression and DNA binding of C/EBP delta. (c) 2006 Elsevier Inc. All rights reserved.