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J Immunol 2005 Sep 15;175(6):3964-70

Th1-Like Cytokine Induction by Heat-Killed Brucella abortus Is Dependent on Triggering of TLR9.

Huang LY, Ishii KJ, Akira S, Aliberti J, Golding B

Golding B, US FDA, Div Hematol, Off Blood Res & Review, Ctr Biol Evaluat & Res, Bldg 29,Room 328,1401 Rockville Pike,HFM-345, Rockville, MD 20852 USA US FDA, Div Hematol, Off Blood Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA Osaka Univ, Exploratory Res Adv Technol, Japan Sci & Technol Agcy, Osaka, Japan Osaka Univ, Dept Host Def, Inst Microbial Dis, Osaka, Japan Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27701 USA

Abstract

In this report we provide evidence, for the first time, that bacterial DNA in the context of heat-killed Brucella abortus (HKBA) engages TLR9 in dendritic cells (DC), resulting in a Th1-like cytokine response. This is based on the findings that HKBA induction of IL-12p40 is: 1) abolished in DC from TLR9(-/-) mice; 2) blocked by suppressive oligodeoxynucleotides; 3) simulated by bacterial DNA derived from HKBA; and 4) abrogated by DNase or methylation of the DNA from HKBA. Furthermore, the effect of HKBA can be inhibited by chloroquine, indicating that endosomal acidification is required and supporting the notion that DNA from HKBA is interacting with TLR9 at the level of the endosome, as is the case with CpG oligodeoxynucleotides. In addition to DC, HKBA can elicit IL-12p40 secretion from macrophages, in which case the effect is wholly MyD88 dependent but only partially TLR9 dependent. This probably explains why HKBA effects in vivo are only partially reduced in TLR9(-/-), but absent in MyD88(-/-) mice. Because of their intimate interactions with T cells, the DC response is most likely to be critical for linking innate and adaptive immune responses, whereas the macrophage reaction may play a role in enhancing NK cell and bystander immune responses. In addition to IL-12p40, HKBA induces other Th1-like cytokines, namely, IFN-alpha and IFN-gamma, in a TLR9-dependent manner. These cytokines are important in protection against viruses and bacteria, and their induction enhances HKBA as a potential carrier for vaccines.


Category: Journal Article
PubMed ID: #16148144
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29
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