Abstract
In the last few years, it has been shown that bacterial DNA stimulates and is recognized by cells of the immune system (Wagner 1999). Cell types that have been shown to respond directly to bacterial DNA include cells of the innate immune system, such as macrophages and dendritic cells, as well as B cells. Notably, the pattern of responsive cell types strongly resembles the pattern of cells stimulated by other so-called pattern-recognition factors, such as lipopolysaccharides (LPS). In addition, the spectrum of effects induced by these biochemically different agents are remarkably similar to each other. It includes induction of a variety of soluble factors, upregulation of membrane proteins and regulation of cell proliferation and survival. Due to the profound alterations in the cells’ behaviour upon stimulation by CpG-DNA, it has been compelling to postulate changes in the transcriptional and post-transcriptional activities. How can the information contained in unmethylated CpG-motifs in bacterial DNA be translated into gene expression? One possibility is that CpG-DNA, like other common ligands, engages a specific cellular receptor that transduces the signal by signal transduction pathways from the outside to the nucleus. Recently, it was shown that classic signal transduction pathways, such as the stress-kinase pathway and the nuclear factor ĸB (NF-ĸB) activation pathway, are switched on in response to CpG-DNA. The current knowledge about these pathways in the context of their activation by CpG-DNA and the upstream requirements for signal initiation are discussed in this chapter.
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Abdel-Hafiz HA. Heasley LE, Kyriakis JM, Avruch J, Kroll DJ, Johnson GL, Hoeffler JP (1992) Activating transcription factor-2 DNA-binding activity is stimulated by phosphorylation catalyzed by p42 and p54 microtubule-associated protein kinases. Mol Endocrinol 6: 2079–2089
Baeuerle PA, Henkel T (1994) Function and activation of NF-KB in the immune system. Annu Rev Immunol 12: 141–179
Beninetskaya L, Loike JD, Khaled Z, Loike G, Silverstein SC, Cao L, Khoury J, Cai TQ, Stein CA (1997) Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nat Med 3: 414–420
Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W (1996) The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 15: 1914–1923
Bird TA, Kyriakis JM, Tyshler L, Gayle M, Milne A, Virca GD (1994) Interleukin-1 activates p54 mitogen-activated protein (MAP) kinase/stress-activated protein kinase by a pathway that is independent of p2lras, Raf-1, and MAP kinase kinase. J Biol Chem 269: 31836–31844
Bours V, Franzoso G, Azxrenko V, Park S, Kanno T, Brown K, Siebenlist U (1993) The oncoprotein Bel-3 directly transactivates through KB motifs via association with DNA-binding p50B homodimers. Cell 72: 729–739
Chapman RE, Munro S (1994) Retrieval of TGN proteins from the cell surface requires endosomal acidification. EMBO J 13: 2305–2312
Chen CY, Del Gatto-Konczak F, Wu Z, Karin M (1998) Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 280: 1945–1949
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC (1995) SB 203580 is a specific inhibitor of a MAP-kinase homologue which is stimulated by cellular stresses and interleukin-l. FEBS Lett. 364: 229–233
Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ (1995) Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267: 682–685
DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IKB kinase that activates the transcription factor NF-KB. Nature 388: 548–554
Drouet C, Shakhov AN, Jongeneel CV (1991) Enhancers and transcription factors controlling the induc- ibility of the tumor necrosis factor-a promoter in primary macrophages. J Immunol 147: 1694–1700
Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow MA, Zon LI (1998) SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc Natl Acad Sci USA 95: 6881–6886
Ghosh S, May MJ, Kopp EB (1998) NF-KB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225–260
Grilli M, Chiu JJ, Lenardo MJ (1993) NF-KB and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol 143: 1–62
Gupta S, Campbell D, Derijard B, Davis RJ (1995) Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267: 389–393
Hacker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H (1998) CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J 17: 6230–6240
Hambleton J, Weinstein SL, Lem L, DeFranco AL (1996) Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci USA 93: 2774–2778
Han J, Lee JD, Bibbs L, Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808–811
Hibi M, Lin A, Smeal T, Minden A, Karin M (1993) Identification of an oncoprotein-and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 7: 2135–2148
Hipskind RA, Buscher D, Nordheim A, Baccarini M (1994) Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors. Genes Dev 8: 1803–1816
Hiscott J, Marois J, Garoufalis J, D’Addario M, Roulston A, Kwan I, Pepin N, Lacoste J, Nguyen H, Bensi G (1993) Characterization of a functional NF-K B site in the human interleukin lß promoter: evidence for a positive autoregulatory loop. Mol Cell Biol 13: 6231–6240
Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK) — from inflammation to development. Curr Opin Cell Biol 10: 205–219
Karin M, Liu Zg, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9: 240–246
Karin M (1998) The NF-K B activation pathway: its regulation and role in inflammation and cell survival. Cancer J Sci Am 4 Suppl 1: 592–9
Kimura Y, Sonehara K, Kuramoto E, Makino T, Yamamoto S, Yamamoto T, Kataoka T, Tokunaga T (1994) Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J Biochem (Tokyo) 116: 991–994
Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M (1998) Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med 188: 2091–2097
Kopp EB, Ghosh S (1995) NF-K B and rel proteins in innate immunity. Adv Immunol 58: 1–27
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374: 546–549
Krieg AM, Wu T, Weeratna R, Efler SM, Love-Homan L, Yang L, Yi AK, Short D, Davis HL (1998) Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci USA 95: 12631–12636
Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739–746
Lewis TS, Shapiro PS, Ahn NG (1998) Signal transduction through MAP kinase cascades. Adv Cancer Res 74: 49–139
Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M (1995) Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268: 286–290
Livingstone C, Patel G, Jones N (1995) ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J 14: 1785–1797
Macfarlane DE, Manzel L (1998) Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol 160: 1122–1131
Malinin NL, Boldin MP, Kovalenko AV, Wallach D (1997) MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1. Nature 385: 540–544
Mellman I, Fuchs R, Helenius A (1986) Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55: 663–700
Messina JP, Gilkeson GS, Pisetsky DS (1991) Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol 147: 1759–1764
Muller JM, Rupec RA, Baeuerle PA (1997) Study of gene regulation by NF-KB and AP-1 in response to reactive oxygen intermediates. Methods 11: 301–312
Muroi M, Muroi Y, Suzuki T (1994) The binding of immobilized IgG2a to Fcy2a receptor activates NF-KB via reactive oxygen intermediates and tumor necrosis factor-al. J Biol Chem 269: 30561–30568
Nishina H, Bachmann M, Oliveira-dos-Santos AJ, Kozieradzki I, Fischer KD, Odermatt B, Wakeham A, Shahinian A, Takimoto H, Bernstein A, Mak TW, Woodgett JR, Ohashi PS, Penninger JM (1997) Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. J Exp Med 186: 941–953
Ohkuma S, Poole B (1981) Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances. J Cell Biol 90: 656–664
Pisetsky DS (1996) Immune activation by bacterial DNA: a new genetic code. Immunity 5: 303–310
Poltorak A, He X, Smirnova I, Liu MY, Huffel CV, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/ HeJ and C57BL/10ScCr mice: mutations in TIr4 gene. Science 282: 2085–2088
Pombo CM, Bonventre JV, Avruch J, Woodgett JR, Kyriakis JM, Force T (1994) The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem 269: 26546–26551
Price MA, Rogers AE, Treisman R (1995) Comparative analysis of the ternary complex factors Elk-I, SAP-la and SAP-2 (ERP/NET) EMBO J. 14: 2589–2601
Prichett W, Hand A, Sheilds J, Dunnington D (1995) Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor a. J Inflamm 45: 97–105
Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ (1996) MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 16: 1247–1255
Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (1997) Identification and characterization of an IKB kinase. Cell 90: 373–383
Rincon M. Enslen H, Raingeaud J, Recht M, Zapton T, Su MS, Penix LA, Davis RJ, Flavell RA (1998) Interferon-y expression by Thl effector T cells mediated by the p38 MAP-kinase signaling pathway. EMBO J 17: 2817–2829
Roussel MF (1998) Key effectors of signal transduction and GI progression. Adv Cancer Res 74: 1–24
Sanchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J, Kyriakis JM, Zon LI (1994) Role of SAPK/ERK kinase-I in the stress-activated pathway regulating transcription factor c-Jun. Nature 372: 794–798
Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A. Weber MJ (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281: 1668–1671
Sluss HK, Barrett T, Derijard B, Davis RJ (1994) Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol 14: 8376–8384
Smeal T, Binetruy B, Mercola D, Grover-Bardwick A, Heidecker G, Rapp UR. Karin M (1992) Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Mol Cell Biol 12:3507-3513
Sparwasser T, Miethke T, Lipford G, Erdmann A, Hacker H, Heeg K, Wagner H (1997) Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-a-mediated shock. Eur J Immunol 27: 1671–1679
Stacey KJ, Sweet MJ, Hume DA (1996) Macrophages ingest and are activated by bacterial DNA. J Immunol 157: 2116–2122
Sweet MJ, Hume DA (1996) Endotoxin signal transduction in macrophages. J Leukoc Biol 60: 8–26
Tonkinson JL, Stein CA (1994) Patterns of intracellular compartmentalization, trafficking and acidification of 5’-fluorescein labeled phosphodiester and phosphorothioate oligodeoxynucleotides in HL60 cells. Nucleic Acids Res 22: 4268–4275
Ulevitch RJ (1999) Endotoxin opens the Tollgates to innate immunity [In Process Citation]. Nat Med 5: 144–145
van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P, Zantema A, Angel P, van der Eb AJ (1993) Heterodimer formation of c-Jun and ATF-2 is responsible for induction of c j¢oi by the 243 amino acid adenovirus EIA protein. EMBO J 12: 479–487
Vasquez KM, Wilson JH (1998) Triplex-directed modification of genes and gene activity. Trends Biochem Sci 23: 4–9
Vasquez KM, Wilson JH (1998) Triplex-directed modification of genes and gene activity. Trends Biochem Sci 23: 4–9
Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7: 837–847
Westwick JK, Weitzel C, Minden A, Karin M, Brenner DA (1994) Tumor necrosis factor a stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem 269: 26396–26401
Whitmarsh AJ, Cavanagh J. Tournier C, Yasuda J, Davis RJ (1998) A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281: 1671–1674
Whitmarsh AJ, Davis RJ (1998) Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem Sci 23: 481–485
Wloch MK, Pasquini S, Ertl HC, Pisetsky DS (1998) The influence of DNA sequence on the immunostimulatory properties of plasmidzDNA vectors. Hum Gene Ther 9: 1439–1447
Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ (1998) Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395: 284–288
Yi AK, Klinman DM, Martin TL, Matson S, Krieg AM (1996) Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway. J Immunol 157: 5394–5402
Yi AK, Chang M, Peckham DW, Krieg AM, Ashman RF (1998a) CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. J Immunol 160: 5898–5906
Yi AK, Tuetken R, Redford T, Waldschmidt M, Kirsch J, Krieg AM (1998b) CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol 160: 4755–4761
Yi AK, Krieg AM (1998a) Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. J Immunol 161: 4493–4497
Yi AK, Krieg AM (1998b) CpG DNA rescue from anti-IgM-induced WEHI-231 B lymphoma apoptosis via modulation of IKBa and IKB3 and sustained activation of nuclear factor-K B/c-Rel. J Immunol 160: 1240–1245
Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y (1991) Bafilomycin Al, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem 266: 17707–17712
Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997) The IKB kinase complex ( IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IĸB phosphorylation and NF-KB activation. Cell 91: 243–252
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Häcker, H. (2000). Signal Transduction Pathways Activated by CpG-DNA. In: Wagner, H. (eds) Immunobiology of Bacterial CpG-DNA. Current Topics in Microbiology and Immunology, vol 247. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59672-8_5
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DOI: https://doi.org/10.1007/978-3-642-59672-8_5
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