Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-α production through activation of NF-κB

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Abstract
Unmethylated CpG motifs in bacterial DNA (CpG DNA) activate host innate immune responses synergistically with some other microbial products, such as endotoxins, and may contribute to disease pathogenesis through excessive production of proinflammatory cytokines. Because monocyte-derived tumor necrosis factor (TNF)-α is an important mediator of disease, we investigated whether CpG DNA and lipopolysaccharide (LPS) synergize for inducing TNF-α biosynthesis. CpG DNA and LPS synergistically induce TNF-α production in RAW264.7 cells and J774 cells through activation of NF-κB. Furthermore, transient transfection with a super-repressive mutant of IκBα (IκBα-AA) demonstrated that NF-κB plays a critical role in CpG DNA-mediated TNF-α expression. Like NF-κB activation, CpG DNA-induced activation of mitogen-activated protein kinases (MAPK) regulates TNF-α production. Both extracellular receptor kinase (ERK) and p38 can regulate TNF-α gene transcription induced by CpG DNA. Although CpG DNA at the higher concentration slightly enhanced LPS-mediated phosphorylation of ERK, it did not alter the LPS-mediated activation of c-Jun N-terminal kinase and p38. In addition, CpG DNA showed little or no enhancement of LPS-mediated AP-1 activation. These results suggest that CpG DNA- and LPS-mediated signals converge at or above the level of NF-κB and ERK, and that there are distinct, as well as common, signaling pathways which are utilized by both CpG DNA and LPS for activating various transcription factors and MAPK.

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