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Infection and Immunity, December 2000, p. 6883-6890, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Involvement of Toll-Like Receptors

Shoutaro Tsuji,1,2 Misako Matsumoto,1,2 Osamu Takeuchi,3 Shizuo Akira,3 Ichiro Azuma,4,dagger Akira Hayashi,1,2 Kumao Toyoshima,1 and Tsukasa Seya1,2,*

Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511,1 Institute of Immunological Science, Hokkaido University, Kita-ku, Sapporo 060,4 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565,3 and Organization for Pharmaceutical Safety and Research, Tokyo 100-0013,2 Japan

Received 3 August 2000/Accepted 15 September 2000

The constituents of mycobacteria are an effective immune adjuvant, as observed with complete Freund's adjuvant. In this study, we demonstrated that the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin (BCG-CWS), a purified noninfectious material consisting of peptidoglycan, arabinogalactan, and mycolic acids, induces maturation of human dendritic cells (DC). Surface expression of CD40, CD80, CD83, and CD86 was increased by BCG-CWS on human immature DC, and the effect was similar to those of interleukin-1beta (IL-1beta ), tumor necrosis factor alpha (TNF-alpha ), heat-killed BCG, and viable BCG. BCG-CWS induced the secretion of TNF-alpha , IL-6, and IL-12 p40. CD83 expression was increased by a soluble factor secreted from BCG-CWS-treated DC and was completely inhibited by monoclonal antibodies against TNF-alpha . BCG-CWS-treated DC stimulated extensive allogeneic mixed lymphocyte reactions. The level of TNF-alpha secreted through BCG-CWS was partially suppressed in murine macrophages with no Toll-like receptor 2 (TLR 2) or TLR4 and was completely lost in TLR2 and TLR4 double-deficient macrophages. These results suggest that the BCG-CWS induces TNF-alpha secretion from DC via TLR2 and TLR4 and that the secreted TNF-alpha induces the maturation of DC per se.

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

dagger Present address: Hakodate National College of Technology, Hakodate 042-8501, Japan.

Infection and Immunity, December 2000, p. 6883-6890, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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