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Veterans Administration Medical Center, Iowa City, IA 52242; and Divisions of
Pulmonary, Critical Care, and Occupational Medicine, and
Rheumatology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
To determine whether the systemic immune activation by CpG DNA
could alter airway inflammation, we pretreated mice with either i.v.
bacterial DNA (bDNA) or oligonucleotides with or without CpG motifs,
exposed these mice to LPS by inhalation, and measured the inflammatory
response systemically and in the lung immediately following LPS
inhalation. Compared with non-CpG oligonucleotides, i.v. treatment with
CpG oligonucleotides resulted in higher systemic concentrations of
polymorphonuclear leukocytes, IL-10, and IL-12, but significantly
reduced the concentration of total cells, polymorphonuclear leukocytes,
TNF-
, and macrophage inflammatory protein-2 in the lavage fluid
following LPS inhalation. The immunoprotective effect of CpG-containing
oligonucleotides was dose-dependent and was most pronounced in mice
pretreated between 2 and 4 h before the inhalation challenge,
corresponding to the peak levels of serum cytokines. bDNA resulted in a
similar immunoprotective effect, and methylation of the CpG motifs
abolished the protective effect of CpG oligonucleotides. The protective
effect of CpG oligonucleotides was observed in mice with either a
disrupted IL-10 or IFN-
gene, but release of cytokines in the lung
was increased, especially in the mice lacking IFN-. In contrast, CpG
DNA did not protect mice with a disrupted IL-12 gene against the
LPS-induced cellular influx, even though CpG DNA reduced the release of
TNF- and macrophage inflammatory protein-2 in the lung. These
findings indicate that CpG-containing oligonucleotides or bDNA are
protected against LPS-induced cellular airway inflammation through an
IL-12-dependent pathway, and that the pulmonary cytokine and cellular
changes appear to be regulated independently.
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