Gene-inducing program of human dendritic cells in response to BCG cell-wall skeleton (CWS), which reflects adjuvancy required for tumor immunotherapy

• Published in: Immunology letters 2005-05, Vol.98 (2), p.280-290
• Main Authors: Ishii, Kazuo, Kurita-Taniguchi, Mitsue, Aoki, Mikio, Kimura, Toru, Kashiwazaki, Yasuo, Matsumoto, Misako, Seya, Tsukasa
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Bacillus Calmette-Guerin cell-wall skeleton; Cell Differentiation; Cell Wall Skeleton - immunology; Cells, Cultured; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Interferons - metabolism; Lipopolysaccharides - pharmacology; Microarray; Mycobacterium bovis - immunology; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; Peptidoglycan - pharmacology; Phenotype; RNA, Messenger - genetics; Toll-like receptor; Up-Regulation
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2004.12.002

Adjuvants induce the expression of a number of genes in dendritic cells (DCs), which facilitate effective antigen-presentation and cytokine/chemokine liberation. It has been accepted that the toll-like receptor (TLR) family governs the adjuvant activity in DCs. An adjuvant with a long history is mycobacteria in an oil-in-water emulsion, namely Freund's complete adjuvant. Since the active center for the adjuvancy in mycobacteria is the cell-wall skeleton (CWS), we used the bacillus Calmette-Guérin cell-wall skeleton (BCG-CWS) to test DC maturation by GeneChip™ analysis. We identified the genes supporting an efficient DC response and output. Approximately 2000 genes were up-regulated by BCG-CWS stimulation. BCG-CWS-, peptidoglycan (PGN)- and lipopolysaccharide (LPS)-stimulation generally up-regulated some gene clusters including genes for inflammatory cytokines (TNF, IL1α, IL1β, IL6, IL12 p40, IL23 p19, etc.), chemokines (CCL20, IL8, etc.), cell adhesion molecules (ICAM-1, etc.), apoptosis-related proteins (GADD45B, BCL2A1, etc.), metabolic enzymes (PTGS2, SOD2, etc.) and miscellaneous proteins (EHD1, TNFAIP6, etc.). LPS-stimulation, but not BCG-CWS- or PGN-stimulation, up-regulated the interferon-inducible antiviral proteins, including IFIT1, IFIT2, IFIT4, CXCL10, ISG15, OASL, IFITM1 and MX1. We also found that the BCG-CWS- or PGN-stimulation up-regulated CXCL5, MMP1, etc. We discussed their properties in association with TLRs and recently discovered TLR adapters.