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Infection and Immunity, August 2003, p. 4238-4249, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4238-4249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Simultaneous Blocking of Human Toll-Like Receptors 2 and 4 Suppresses Myeloid Dendritic Cell Activation Induced by Mycobacterium bovis Bacillus Calmette-Guérin Peptidoglycan

Junji Uehori,1,2 Misako Matsumoto,1,3 Shoutaro Tsuji,1,3 Takashi Akazawa,1,3 Osamu Takeuchi,4 Shizuo Akira,4 Tsutomu Kawata,5 Ichiro Azuma,6 Kumao Toyoshima,1 and Tsukasa Seya1,2,3*

Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511,1 Department of Molecular Immunology, Nara Institute Science and Technology, Ikoma, Nara 630-0101,2 Organization for Pharmaceutical Safety and Research, Tokyo 100-0013,3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871,4 Tsukuba Research Laboratories, Eisai Co. Ltd., Tsukuba-shi, Ibaraki 300-2635,5 Hakodate National College of Technology, Tokura 14-1, Hakodate 042-8501, Japan6

Received 10 January 2003/ Returned for modification 19 February 2003/ Accepted 8 April 2003

The Mycobacterium bovis bacillus Calmette-Guérin (BCG) cell wall skeleton (CWS) consists of mycolic acids, arabinogalactan, and peptidoglycan (PGN) and activates Toll-like receptor 2 (TLR2) and TLR4. Here we investigated the ability of the essential portion of highly purified BCG CWS to support the TLR agonist function by using the following criteria: myeloid dendritic cell (DC) maturation, i.e., tumor necrosis factor alpha (TNF-{alpha}) production and CD83/CD86 up-regulation. The purified PGN region was sufficient to activate TLR2 and TLR4 in mouse DCs and macrophages; in TLR2 and TLR4 double-knockout cells the BCG PGN-mediated TNF-{alpha} production ability was completely impaired. Likewise, stimulation with BCG CWS of HEK293 cells expressing either human TLR2 or TLR4, MD-2, and CD14 resulted in NF-{kappa}B activation as determined by a reporter assay. Notably, specific blockers of extracellular human TLR2 (an original cocktail of monoclonal antibodies TLR2.45 and TH2.1) and TLR4 (E5531) inhibited BCG CWS-mediated NF-{kappa}B activation by 80%. Using this human TLR blocking system, we tested whether human myeloid DC maturation was TLR2 and TLR4 dependent. BCG PGN-mediated DC maturation was blocked by 70% by suppression of both TLR2 and TLR4 and by 30 to 40% by suppression of either of these TLRs. Similar but less profound suppression of BCG CWS-mediated DC maturation was observed. Hence, the presence of BCG PGN is a minimal requirement for activation of both TLR2 and TLR4 in human DCs, unlike the presence of PGNs of gram-positive bacteria, which activate only TLR2. Unexpectedly, however, BCG PGN, unlike BCG CWS, barely activated NF-{kappa}B in HEK293 cells coexpressing TLR2 plus TLR1, TLR2 plus TLR4, TLR2 plus TLR6, or TLR2 plus TLR10, suggesting that PGN receptors other than TLR2 and TLR4 present on human DCs but not on HEK293 cells are involved in TLR signaling for DC activation.

* Corresponding author. Mailing address: Department of Immunology, Osaka Medical Center for Cancer, Higashinari-ku, Osaka 537-8511, Japan. Phone and fax: 81 6 6973 1209. E-mail: seya-tu{at}mc.pref.osaka.jp.

Editor: S. H. E. Kaufmann

Infection and Immunity, August 2003, p. 4238-4249, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4238-4249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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