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Infection and Immunity, December 1999, p. 6257-6263, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Induction and Regulation of Th1-Inducing Cytokines
by Bacterial DNA, Lipopolysaccharide, and Heat-Inactivated
Bacteria
L.-Y.
Huang,1
A. M.
Krieg,2
N.
Eller,1 and
D. E.
Scott1,*
Center for Biologics Evaluation and Research,
U.S. Food and Drug Administration, Bethesda, Maryland
20892,1 and Department of Internal
Medicine, University of Iowa, Iowa City, Iowa
522422
Received 30 March 1999/Returned for modification 17 July
1999/Accepted 7 September 1999
Th1 immune responses, characterized by production of gamma
interferon (IFN-
), are associated with protective immunity to viruses and intracellular bacteria. Heat-killed Brucella
abortus promotes secretion of Th1-inducing cytokines such as
interleukin-12 (IL-12) and IFN-
and has been used as a carrier to
induce Th1 responses to vaccines. To explore which bacterial
constituents could mediate this response and how it is regulated,
murine spleen cells were cultured with B. abortus derived
DNA, lipopolysaccharide (LPS), or whole killed organisms. Each
constituent induced similar, substantial amounts of IL-10. However,
only B. abortus and B. abortus DNA induced high
levels of IFN-
and IL-12. B. abortus and B. abortus DNA-stimulated IL-12 production was maximal by 6 to
18 h, while IL-10 production steadily accumulated over this time
period. These kinetics suggested that IL-10 may eventually downmodulate
the Th1-like cytokine response to B. abortus and B. abortus DNA, which was confirmed by using neutralizing antibody. In the absence of IL-10, B. abortus LPS induced strong
IFN-
responses, but IL-12 p70 levels were still undetectable from
BALB/c spleen cells. LPS induced IL-12 if the spleen cells were primed
with IFN-
and IL-10 was neutralized, indicating that LPS can
stimulate IL-12 production under the most favorable conditions.
Responses to Escherichia coli LPS and DNA mirrored the
responses to B. abortus components, suggesting that immune
effects observed with these constituents may be generalizable to many
microbial species. In vivo experiments demonstrated the same hierarchy
of responses for IL-12 production. These findings support the
likelihood that microbial components, if used as carriers or adjuvants,
can differ substantially in their ability to effect a Th1 response.
*
Corresponding author. Mailing address: Center for
Biologics Evaluation and Research, FDA, Bldg. 29, Rm. 232, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-3016. Fax: (301)
402-2780. E-mail: scottd{at}cber.fda.gov.
Infection and Immunity, December 1999, p. 6257-6263, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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