Chinese Bulletin of Life Sciences. ZHENG Jie

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1 Chinese Bulletin of Life Sciences Vol. 19, No. 1 Feb., (2007) TLRs To11 To11 To11 To11 R730.3 A Toll-like receptors, chronic inflammation and cancer ZHENG Jie (Institute of Molecular Pathology, Department of Pathology and Pathophysiology, School of Basic Medical Science, Southeast University, Nanjing , China) Abstract: Toll-like receptors play a crucial role in the host defense against invading microorganisms by recognizing pathogen-associated molecular patterns. In addition, it is now known to occur under sterile conditions such as those characterizing autoimmune diseases, cancers, or diseases of unknown cause. Chronic inflammation is recognized to initiate and promote tumor development and progression in various levels. One of mechanisms is the development of an immunosuppressive environment by chronic inflammation in cancer patients, which is also related to Toll-like receptors. Key words: Toll-like receptors; chronic inflammation; cancer 15% [1] T (T-cell receptor, TCR) NK ζ [2-3] To11 (Toll-like receptors TLRs) (patternrecognition receptors) TLRs (pathogen-associated molecular patterns, PAMPs) (pro-inflammatory cytokines) (dendritic cells, DCs) TLRs TLRs (BK ) (1954 ) Tel: , jiezheng54@126.com

2 16 TLRs PAMPs TLRs 1 TLRs TLRs, -1 (IL- 1R) (1eucine-rich repeats, LRRs) 3 (MD-1 MD-2 RPl05) PAMPs IL-1 (IL- 1R) Toll/ IL-1 (Toll/IL-1 receptor, TIR), TLRs IL-1R TLRs PAMPs, PAMPs Toll 11 [4], TLRs TLRl TLR2 TLR6 TLR10, TLR2 TLR7 TLR8 TLR9 TLR9 TLRs TLR2 TLR3 TLR4 DCs 2 TLRs TLRs TLRs TLR1 (peptidoglycans, PGN) (lipopolysaccharide, LPS) TLR2 PAMPs (lipoteichoic acid, LTA) PGN TLR3 RNA (dsrna) poly(i:c); TLR4 LPS (heat shock proteins, HSPs) TLR5 TLR6 PGN TLR7 TLR8 RNA (ssrna) ( ) imidazoquinolines resiquimod imiquimod; TLR9 CpG DNA TLR10 TLR11 Profilin, TLRs TLR1/2 (tri-acyl lipopeptides) TLR2/6 TLRs TLRs PAMPs TLRs HSPs (extracellular matrix, ECM) HSPs HSPs TLRs HSPs HSPs TNF-α IL-1 IL-6 IL-12 (PG) (nitric oxide, NO) ECM, A TLR4 DCs mrna DNA TLR3 TLR9 [5-6] TLRs TLRs ζ T NK TLRs PAMPs HSP60 HSP70 LPS LPS TLR2 TLR4 TLRs TLRs [7] 3 TLRs TLRs TLRs, (adaptor) 88 (MyD88) MyD88 (Mal) Toll (TRIF) Toll (TRAM) NF-κB MAPKs (mitogen-activated protein kinases) -β (IFN-β) (antigen-presenting cells, APCs) CD80 (B7-1) CD86 (B7-2)

3 1 TLRs 17 TLRs TLRs MyD88, TLRs MyD88 MyD88 NF-κB MAPKs NF-κB -3 (IRF-3) ( 1) PAMPs TLR MyD88 TLR4 LPS LPS (LPS-binding protein, LBP) CD14 LPS/LBP/CD14 TLR4 MD-2 TLR4 MyD88 MyD88 MyD88 C TIR N (death domain, DD) TLRs TIR MyD88 MyD88 DD IRAK4 (IL-1R associated kinase 4) DD IRAK4 MyD88 IRAK4 6 (TRAF6) TRAF6 IκB (inhibitor κb) IκB - NF-κB NF-κB ( TNF-α IL ) (CD80 CD86) NF-κB NF-κB NF-κB TLR TIR Mal ( TIRAP) TLR1/2 TLR2 TLR2/ 6 TLR4 MyD88 TLR5 7 9 Mal TLRs TIR TRIF (TIR-domain containing adaptor 1 TLR [6]

4 18 inducing IFN-β) TRAM (Trif-related adaptor molecule) MyD88 TRIF TLR3 TLR4 NF-κB IRF-3 IFN-β TLR3 MyD88 MyD88 TLR3 poly (I:C) NF-κB [8] 4 TLR [1] 4.1 (reactive oxygen species, ROS) (reactive nitrogen species, RNS) (pro-inflammation) (anti-inflammation), IL-1 TNF-α IFN-γ IL-1 IL-10 IL-13 TNF-α TNF-α TNF-α [9] TNF-α NF-κB DNA NO (peroxynitrite, ONOO, ) 8- (8-oxoG, ) 8-oxoG DNA 8- oxog PGE2 TLRs LPS [3,10] 4.2 PAMPs BCG BCG BCG PAMPs TLRs TLR2 TLR4 [11-12] OK-432 OK-432 A OK-432 OK-432 ( OK- PSA) OK-PSA TLR4 [12] DNA, DNA, CpG, DNA CpG (CpG-ODNs) TLR9 [6] CpG-ODNs [13] imidazoquinolines loxoribine broprimine TLR7 [14] PAMPs TLRs, TLR4 60% TLR4 TLR4 TLR4 [15] 4.3 T NK ζ [2-3] ζ TCR(T cell receptor) TCR T NK ζ 3 ITAMs

5 1 TLRs 19 (immnunoreceptor tyrosine-based activation motifs) TCR ITAMs ζ TCR NK T ζ [3,16] ζ T NK ζ ζ (myeloid suppressor cells, MSCs) ζ [3] MSCs T MSCs 2 (NOS2) NO L- L- NO T T L- MSCs T L- L- TCR ζ [17] L- T MSCs IFNγ IFNγ MSCs [3] MSCs MSCs T MSCs MSCs ζ T (superactivated) ζ MSCs ζ [18] ζ ROS RNS ζ [19] NO T [20] T ζ (tumor infiltrating lymphocytes, TILs) T ζ [21] T ζ ζ ζ ζ HSPs ECM A TLRs MSCs ζ TLRs PAMPs TLRs [7] 5 TLRs PAMPs, TLRs MSCs T NK ζ T NK [1] Coussens L M, Werb Z. Inflammation and cancer. Nature, 2002, 420: [2] Baniyash M. TCR chain downregulation: curtaining excessive inflammatory immune response. Nat Rev Immunol, 2004, 4: [3] Baniyash M. Chronic inflammation, immunosuppression and cancer: new insights and outlook. Semin Cancer Biol, 2006, 16: [4] Agrawal S, Kandimalla E R. Medicinal chemistry and therapeutic potential of CpG DNA. Trend Mol Med, 2002, 8: [5] Kariko K, Ni H, Capodici J, et al. mrna is an endogenous ligand for Toll-like receptor 3. J Biol Chem, 2004, 279: [6] Ishii K J, Akira S. Innate immune recognition of nucleic acids: beyond toll-like receptors. Int J Cancer, 2005, 117: [7] Beutler B. Inferences, questions and possibilities in Toll-

6 20 like receptor signalling. Nature, 2004, 430(6996): [8] Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol, 2004, 4: [9] De Visser K E, Eichten A, Coussens L M. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer, 2006, 6: [10] Wang J H, Manning B J, Wu Q D, et al. Endotoxin/lipopolysaccharide activates NF-κB and enhances tumor cell adhesion and invasion through a β1 integrin dependent mechanism. J Immunol, 2003, 170(2): [11] Tsuji S, Matsumoto M, Takeuchi O, et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of Tolllike receptors. Infect Immun, 2000, 68: [12] Okamoto M, Oshikawa T, Tano T, et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and Toll-like receptor 4 signaling. J Immunother, 2006, 29(1): [13] Milas L, Mason K A, Ariga H, et al. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res, 2004, 64: [14] Hemmi H, Kaisho T, Takeuchi O, et al. Small antiviral compounds activate immune cells via TLR7 MyD88-dependent signaling pathway. Nat Immunol, 2002, 3: [15] Bauer A K, Dixon D, DeGraff L M, et al. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst, 2005, 97: [16] Kuss I, Saito T, Johnson J T, et al. Clinical significance of decreased ζ chain expression in peripheral blood lymphocytes of patients with head and neck cancer. Clin Cancer Res, 1999, 5(2): [17] Rodriguez P C, Zea A H, DeSalvo J, et al. L-arginine consumption by macrophages modulates the expression of CD3 ζ chain in T lymphocytes. J Immunol, 2003, 171(3): [18] Taylor D D, Bender D P, Gercel-Taylor C, et al. Modulation of TcR/CD3-ζ chain expression by a circulating factor derived from ovarian cancer patients. Br J Cancer, 2001, 84(12): [19] Kono K, Salazar-Onfray F, Petersson M, et al. Hydrogen peroxide secreted by tumor-derived macrophages downmodulates signal-transducing ζ molecules and inhibits tumorspecific T cell and natural killer cell-mediated cytotoxicity. Eur J Immunol, 1996, 26: [20] Mazzoni A, Bronte V, Visintin A, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol, 2002, 168: [21] Whiteside T L. Down-regulation of ζ-chain expression in T cells: a biomarker of prognosis in cancer? Cancer Immunol Immunother, 2004, 29: 29 Introduction to Plant Tissue Culture [ ] M.K. (M.K.Razdan) M.K

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