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PMID: 14742539 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mycobacterium bovis BCG cell wall-specific differentially expressed genes identified by differential display and cDNA subtraction in human macrophages.

Infection and immunity ·Vol. 72 ·No. 2 ·2004-02-00 ·Pages 937-48

Begum NA, Ishii K, Kurita-Taniguchi M, Tanabe M, Kobayashi M, Moriwaki Y, Matsumoto M, Fukumori Y, Azuma I, Toyoshima K, Seya T

Abstract

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.

MeSH Terms
Adjuvants, Immunologic/pharmacology Base Sequence Cell Wall Skeleton/pharmacology Cytokines/genetics Dendritic Cells/physiology Gene Expression Profiling Gene Library Humans Lipopolysaccharides/pharmacology Macrophages/metabolism Membrane Glycoproteins/genetics Membrane Proteins/genetics Molecular Sequence Data Monocytes/metabolism Mycobacterium bovis/immunology Oligonucleotide Array Sequence Analysis Receptors, Cell Surface/genetics Receptors, Immunologic/genetics Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors Transcription, Genetic Triggering Receptor Expressed on Myeloid Cells-1
Chemicals
Adjuvants, Immunologic BCG lipopolysaccharide Cell Wall Skeleton Cytokines Lipopolysaccharides Membrane Glycoproteins Membrane Proteins Receptors, Cell Surface Receptors, Immunologic TLR2 protein, human TLR4 protein, human TREM1 protein, human Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors Triggering Receptor Expressed on Myeloid Cells-1
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Begum Nasim A
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan.
Ishii Kazuo
Kurita-Taniguchi Mitsue
Tanabe Masako
Kobayashi Mika
Moriwaki Yasuhiro
Matsumoto Misako
Fukumori Yasuo
Azuma Ichiro
Toyoshima Kumao
Seya Tsukasa
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Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.72.2.937-948.2004
Published
2004-02-00
Pages
937-48
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC321570
Subset
IM
External Links
PubMed source DOI: 10.1128/IAI.72.2.937-948.2004 PMC Full Text View journal details
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