Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway.
Unmethylated CpG dinucleotides (CpG motif) in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) rapidly activate murine B cells to secrete IL-6 and IgM, as well as to proliferate. Within 30 min after CpG DNA stimulation in vivo, IL-6 mRNA levels were increased in liver, spleen, and thymus cells. Serum IL-6 protein was markedly increased within 1 h of stimulation. Treatment of a B cell line with CpG DNA led to an increase in the transcriptional activity of the IL-6 promoter. This CpG DNA-induced IL-6 production was not mediated via either a protein kinase C (PKC)-, protein kinase A (PKA)-, or nitric oxide (NO.)-dependent pathway but was inhibited by an antioxidant. In addition, the level of intracellular reactive oxygen species was increased within 20 min after CpG DNA, but not control non-CpG DNA, treatment. These results suggest that CpG DNA-induced IL-6 production is mediated through a reactive oxygen intermediate-dependent pathway. CpG DNA-mediated IL-6 production was enhanced by simultaneous signals delivered through the Ag receptor. The addition of neutralizing Abs against IL-6 to B cell cultures along with CpG oligodeoxynucleotides essentially abolished the CpG DNA-induced increased IgM secretion but had no significant effect on the B cell proliferation induced by the CpG motif. Our results suggest that the induction of IL-6 expression in response to CpG motifs in bacterial DNA may be an important immune defense mechanism that facilitates a rapid response to microbial infection.
Yi
A K
AK
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Klinman
D M
DM
Martin
T L
TL
Matson
S
S
Krieg
A M
AM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D004269:DNA, Bacterial / Q000276:immunology*; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic
D000975:Antioxidants; D004269:DNA, Bacterial; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell