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Infection and Immunity, February 2004, p. 937-948, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.937-948.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mycobacterium bovis BCG Cell Wall-Specific Differentially Expressed Genes Identified by Differential Display and cDNA Subtraction in Human Macrophages

Nasim A. Begum,1,{dagger} Kazuo Ishii,1,{dagger} Mitsue Kurita-Taniguchi,1 Masako Tanabe,1 Mika Kobayashi,1,2 Yasuhiro Moriwaki,1,2 Misako Matsumoto,1 Yasuo Fukumori,3 Ichiro Azuma,4 Kumao Toyoshima,1 and Tsukasa Seya1,2*

Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511,1 Department of Molecular Immunology, Nara Institute of Science and Technology Ikoma, Nara 631-0101,2 Osaka Red Cross Blood Center, Osaka Johtoh-ku, Osaka 537,3 Hakodate National College of Technology, Tokura 14-1, Hakodate 042-8501, Japan4

Received 31 March 2003/ Returned for modification 26 May 2003/ Accepted 15 October 2003

We have analyzed the gene expression profile of monocytes in response to a highly purified cell wall fraction of Mycobacterium bovis BCG, a clinically approved adjuvant known as BCG cell wall skeleton (BCG-CWS). It is composed of mycolic acid, arabinogalactan, and peptidoglycan and confers Toll-like receptor 2 (TLR2)- and TLR4-dependent signaling that induces monocytes to differentiate into antigen-presenting cells (APCs). Here we report differential gene expression analysis with BCG-CWS-stimulated versus nonstimulated monocytes. BCG-CWS exerted massive induction of genes regulated by TLR signaling. Marked gene regulatory characteristics in BCG-CWS-stimulated cells compared to lipopolysaccharide (LPS)-stimulated cells follow. (i) Spliced mRNAs encoding soluble forms of TREM-1 and TREM-2 (recently discovered inflammatory-signal-amplifying receptors) were regulated by BCG-CWS, resulting in their differential expression. (ii) The genes for zinc-iron transporter protein (ZIP)-like family proteins HKE-1 and LIV-1 were induced exclusively by BCG-CWS. (iii) Interleukin-23 (IL-23), rather than IL-12p70, was induced by BCG-CWS, while interferon-inducible genes were induced only by LPS. By Northern and reverse transcription-PCR analyses, we confirmed the differential expression of more than 30 BCG-CWS regulatory genes, and their expression was compared with that of LPS and other known TLR ligands. A battery of genes responded rapidly and for a short time to LPS but for a long time to BCG-CWS. Structural analysis of the identified novel or hypothetical proteins revealed that some are potential candidates as signaling mediators or transcriptional regulators. Hence, BCG-CWS may profoundly modulate APC responses in a way distinct from that of LPS, leading to possible advantages for its adjuvant-active therapeutic potential.

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

Editor: S. H. E. Kaufmann

{dagger} N.A.B. and K.I. contributed equally to this work.

Infection and Immunity, February 2004, p. 937-948, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.937-948.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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