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. 1998 Nov 2;17(21):6230–6240. doi: 10.1093/emboj/17.21.6230

CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation.

H Häcker 1, H Mischak 1, T Miethke 1, S Liptay 1, R Schmid 1, T Sparwasser 1, K Heeg 1, G B Lipford 1, H Wagner 1
PMCID: PMC1170949  PMID: 9799232

Abstract

Unmethylated CpG motifs in bacterial DNA, plasmid DNA and synthetic oligodeoxynucleotides (CpG ODN) activate dendritic cells (DC) and macrophages in a CD40-CD40 ligand-independent fashion. To understand the molecular mechanisms involved we focused on the cellular uptake of CpG ODN, the need for endosomal maturation and the role of the stress kinase pathway. Here we demonstrate that CpG-DNA induces phosphorylation of Jun N-terminal kinase kinase 1 (JNKK1/SEK/MKK4) and subsequent activation of the stress kinases JNK1/2 and p38 in murine macrophages and dendritic cells. This leads to activation of the transcription factor activating protein-1 (AP-1) via phosphorylation of its constituents c-Jun and ATF2. Moreover, stress kinase activation is essential for CpG-DNA-induced cytokine release of tumor necrosis factor alpha (TNFalpha) and interleukin-12 (IL-12), as inhibition of p38 results in severe impairment of this biological response. We further demonstrate that cellular uptake via endocytosis and subsequent endosomal maturation is essential for signalling, since competition by non-CpG-DNA or compounds blocking endosomal maturation such as chloroquine or bafilomycin A prevent all aspects of cellular activation. The data suggest that endosomal maturation is required for translation of intraendosomal CpG ODN sequences into signalling via the stress kinase pathway, where p38 kinase activation represents an essential step in CpG-ODN-triggered activation of antigen-presenting cells.

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Selected References

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  1. Benimetskaya L., Loike J. D., Khaled Z., Loike G., Silverstein S. C., Cao L., el Khoury J., Cai T. Q., Stein C. A. Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nat Med. 1997 Apr;3(4):414–420. doi: 10.1038/nm0497-414. [DOI] [PubMed] [Google Scholar]
  2. Beyaert R., Cuenda A., Vanden Berghe W., Plaisance S., Lee J. C., Haegeman G., Cohen P., Fiers W. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J. 1996 Apr 15;15(8):1914–1923. [PMC free article] [PubMed] [Google Scholar]
  3. Bird A. P. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. doi: 10.1038/321209a0. [DOI] [PubMed] [Google Scholar]
  4. Bird T. A., Kyriakis J. M., Tyshler L., Gayle M., Milne A., Virca G. D. Interleukin-1 activates p54 mitogen-activated protein (MAP) kinase/stress-activated protein kinase by a pathway that is independent of p21ras, Raf-1, and MAP kinase kinase. J Biol Chem. 1994 Dec 16;269(50):31836–31844. [PubMed] [Google Scholar]
  5. Branda R. F., Moore A. L., Mathews L., McCormack J. J., Zon G. Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1. Biochem Pharmacol. 1993 May 25;45(10):2037–2043. doi: 10.1016/0006-2952(93)90014-n. [DOI] [PubMed] [Google Scholar]
  6. Cella M., Engering A., Pinet V., Pieters J., Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature. 1997 Aug 21;388(6644):782–787. doi: 10.1038/42030. [DOI] [PubMed] [Google Scholar]
  7. Chapman R. E., Munro S. Retrieval of TGN proteins from the cell surface requires endosomal acidification. EMBO J. 1994 May 15;13(10):2305–2312. doi: 10.1002/j.1460-2075.1994.tb06514.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chu R. S., Targoni O. S., Krieg A. M., Lehmann P. V., Harding C. V. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med. 1997 Nov 17;186(10):1623–1631. doi: 10.1084/jem.186.10.1623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cockerill P. N., Bert A. G., Jenkins F., Ryan G. R., Shannon M. F., Vadas M. A. Human granulocyte-macrophage colony-stimulating factor enhancer function is associated with cooperative interactions between AP-1 and NFATp/c. Mol Cell Biol. 1995 Apr;15(4):2071–2079. doi: 10.1128/mcb.15.4.2071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cuenda A., Rouse J., Doza Y. N., Meier R., Cohen P., Gallagher T. F., Young P. R., Lee J. C. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 1995 May 8;364(2):229–233. doi: 10.1016/0014-5793(95)00357-f. [DOI] [PubMed] [Google Scholar]
  11. Davis H. L., Weeratna R., Waldschmidt T. J., Tygrett L., Schorr J., Krieg A. M., Weeranta R. CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol. 1998 Jan 15;160(2):870–876. [PubMed] [Google Scholar]
  12. Dendorfer U., Oettgen P., Libermann T. A. Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol. 1994 Jul;14(7):4443–4454. doi: 10.1128/mcb.14.7.4443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dérijard B., Raingeaud J., Barrett T., Wu I. H., Han J., Ulevitch R. J., Davis R. J. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. doi: 10.1126/science.7839144. [DOI] [PubMed] [Google Scholar]
  14. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  15. Hambleton J., Weinstein S. L., Lem L., DeFranco A. L. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2774–2778. doi: 10.1073/pnas.93.7.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Han J., Lee J. D., Bibbs L., Ulevitch R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. doi: 10.1126/science.7914033. [DOI] [PubMed] [Google Scholar]
  17. Han J., Lee J. D., Tobias P. S., Ulevitch R. J. Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem. 1993 Nov 25;268(33):25009–25014. [PubMed] [Google Scholar]
  18. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  19. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec 1;176(6):1693–1702. doi: 10.1084/jem.176.6.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Karin M., Liu Z. g., Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997 Apr;9(2):240–246. doi: 10.1016/s0955-0674(97)80068-3. [DOI] [PubMed] [Google Scholar]
  21. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995 Jul 14;270(28):16483–16486. doi: 10.1074/jbc.270.28.16483. [DOI] [PubMed] [Google Scholar]
  22. Kieser A., Kilger E., Gires O., Ueffing M., Kolch W., Hammerschmidt W. Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the c-Jun N-terminal kinase cascade. EMBO J. 1997 Nov 3;16(21):6478–6485. doi: 10.1093/emboj/16.21.6478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kimura Y., Sonehara K., Kuramoto E., Makino T., Yamamoto S., Yamamoto T., Kataoka T., Tokunaga T. Binding of oligoguanylate to scavenger receptors is required for oligonucleotides to augment NK cell activity and induce IFN. J Biochem. 1994 Nov;116(5):991–994. doi: 10.1093/oxfordjournals.jbchem.a124658. [DOI] [PubMed] [Google Scholar]
  24. Klinman D. M., Yamshchikov G., Ishigatsubo Y. Contribution of CpG motifs to the immunogenicity of DNA vaccines. J Immunol. 1997 Apr 15;158(8):3635–3639. [PubMed] [Google Scholar]
  25. Krieg A. M., Yi A. K., Matson S., Waldschmidt T. J., Bishop G. A., Teasdale R., Koretzky G. A., Klinman D. M. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995 Apr 6;374(6522):546–549. doi: 10.1038/374546a0. [DOI] [PubMed] [Google Scholar]
  26. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  27. Lee J. C., Laydon J. T., McDonnell P. C., Gallagher T. F., Kumar S., Green D., McNulty D., Blumenthal M. J., Heys J. R., Landvatter S. W. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22;372(6508):739–746. doi: 10.1038/372739a0. [DOI] [PubMed] [Google Scholar]
  28. Liang H., Nishioka Y., Reich C. F., Pisetsky D. S., Lipsky P. E. Activation of human B cells by phosphorothioate oligodeoxynucleotides. J Clin Invest. 1996 Sep 1;98(5):1119–1129. doi: 10.1172/JCI118894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  30. Lipford G. B., Bauer M., Blank C., Reiter R., Wagner H., Heeg K. CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: a new class of vaccine adjuvants. Eur J Immunol. 1997 Sep;27(9):2340–2344. doi: 10.1002/eji.1830270931. [DOI] [PubMed] [Google Scholar]
  31. Lipford G. B., Sparwasser T., Bauer M., Zimmermann S., Koch E. S., Heeg K., Wagner H. Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines. Eur J Immunol. 1997 Dec;27(12):3420–3426. doi: 10.1002/eji.1830271242. [DOI] [PubMed] [Google Scholar]
  32. Livingstone C., Patel G., Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785–1797. doi: 10.1002/j.1460-2075.1995.tb07167.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Macfarlane D. E., Manzel L. Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol. 1998 Feb 1;160(3):1122–1131. [PubMed] [Google Scholar]
  35. Mellman I., Fuchs R., Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem. 1986;55:663–700. doi: 10.1146/annurev.bi.55.070186.003311. [DOI] [PubMed] [Google Scholar]
  36. Messina J. P., Gilkeson G. S., Pisetsky D. S. Stimulation of in vitro murine lymphocyte proliferation by bacterial DNA. J Immunol. 1991 Sep 15;147(6):1759–1764. [PubMed] [Google Scholar]
  37. Murphy T. L., Cleveland M. G., Kulesza P., Magram J., Murphy K. M. Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol. 1995 Oct;15(10):5258–5267. doi: 10.1128/mcb.15.10.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ohkuma S., Poole B. Cytoplasmic vacuolation of mouse peritoneal macrophages and the uptake into lysosomes of weakly basic substances. J Cell Biol. 1981 Sep;90(3):656–664. doi: 10.1083/jcb.90.3.656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pietersma A., Tilly B. C., Gaestel M., de Jong N., Lee J. C., Koster J. F., Sluiter W. p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. Biochem Biophys Res Commun. 1997 Jan 3;230(1):44–48. doi: 10.1006/bbrc.1996.5886. [DOI] [PubMed] [Google Scholar]
  40. Pisetsky D. S. Immune activation by bacterial DNA: a new genetic code. Immunity. 1996 Oct;5(4):303–310. doi: 10.1016/s1074-7613(00)80256-3. [DOI] [PubMed] [Google Scholar]
  41. Prichett W., Hand A., Sheilds J., Dunnington D. Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor alpha. J Inflamm. 1995;45(2):97–105. [PubMed] [Google Scholar]
  42. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  43. Raingeaud J., Whitmarsh A. J., Barrett T., Dérijard B., Davis R. J. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247–1255. doi: 10.1128/mcb.16.3.1247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ray A., Sassone-Corsi P., Sehgal P. B. A multiple cytokine- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. Mol Cell Biol. 1989 Dec;9(12):5537–5547. doi: 10.1128/mcb.9.12.5537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rincón M., Enslen H., Raingeaud J., Recht M., Zapton T., Su M. S., Penix L. A., Davis R. J., Flavell R. A. Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO J. 1998 May 15;17(10):2817–2829. doi: 10.1093/emboj/17.10.2817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Roman M., Martin-Orozco E., Goodman J. S., Nguyen M. D., Sato Y., Ronaghy A., Kornbluth R. S., Richman D. D., Carson D. A., Raz E. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med. 1997 Aug;3(8):849–854. doi: 10.1038/nm0897-849. [DOI] [PubMed] [Google Scholar]
  47. Sato Y., Roman M., Tighe H., Lee D., Corr M., Nguyen M. D., Silverman G. J., Lotz M., Carson D. A., Raz E. Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science. 1996 Jul 19;273(5273):352–354. doi: 10.1126/science.273.5273.352. [DOI] [PubMed] [Google Scholar]
  48. Schmid R. M., Perkins N. D., Duckett C. S., Andrews P. C., Nabel G. J. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. doi: 10.1038/352733a0. [DOI] [PubMed] [Google Scholar]
  49. Shimada S., Yano O., Inoue H., Kuramoto E., Fukuda T., Yamamoto H., Kataoka T., Tokunaga T. Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors. J Natl Cancer Inst. 1985 Mar;74(3):681–688. [PubMed] [Google Scholar]
  50. Sluss H. K., Barrett T., Dérijard B., Davis R. J. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994 Dec;14(12):8376–8384. doi: 10.1128/mcb.14.12.8376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Smeal T., Binetruy B., Mercola D. A., Birrer M., Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature. 1991 Dec 12;354(6353):494–496. doi: 10.1038/354494a0. [DOI] [PubMed] [Google Scholar]
  52. Smeal T., Binetruy B., Mercola D., Grover-Bardwick A., Heidecker G., Rapp U. R., Karin M. Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Mol Cell Biol. 1992 Aug;12(8):3507–3513. doi: 10.1128/mcb.12.8.3507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sparwasser T., Koch E. S., Vabulas R. M., Heeg K., Lipford G. B., Ellwart J. W., Wagner H. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol. 1998 Jun;28(6):2045–2054. doi: 10.1002/(SICI)1521-4141(199806)28:06<2045::AID-IMMU2045>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  54. Sparwasser T., Miethke T., Lipford G., Borschert K., Häcker H., Heeg K., Wagner H. Bacterial DNA causes septic shock. Nature. 1997 Mar 27;386(6623):336–337. doi: 10.1038/386336a0. [DOI] [PubMed] [Google Scholar]
  55. Sparwasser T., Miethke T., Lipford G., Erdmann A., Häcker H., Heeg K., Wagner H. Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock. Eur J Immunol. 1997 Jul;27(7):1671–1679. doi: 10.1002/eji.1830270712. [DOI] [PubMed] [Google Scholar]
  56. Stacey K. J., Sweet M. J., Hume D. A. Macrophages ingest and are activated by bacterial DNA. J Immunol. 1996 Sep 1;157(5):2116–2122. [PubMed] [Google Scholar]
  57. Su B., Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996 Jun;8(3):402–411. doi: 10.1016/s0952-7915(96)80131-2. [DOI] [PubMed] [Google Scholar]
  58. Sved J., Bird A. The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4692–4696. doi: 10.1073/pnas.87.12.4692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
  60. Tanaka T., Chu C. C., Paul W. E. An antisense oligonucleotide complementary to a sequence in I gamma 2b increases gamma 2b germline transcripts, stimulates B cell DNA synthesis, and inhibits immunoglobulin secretion. J Exp Med. 1992 Feb 1;175(2):597–607. doi: 10.1084/jem.175.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Tonkinson J. L., Stein C. A. Patterns of intracellular compartmentalization, trafficking and acidification of 5'-fluorescein labeled phosphodiester and phosphorothioate oligodeoxynucleotides in HL60 cells. Nucleic Acids Res. 1994 Oct 11;22(20):4268–4275. doi: 10.1093/nar/22.20.4268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Torres C. A., Iwasaki A., Barber B. H., Robinson H. L. Differential dependence on target site tissue for gene gun and intramuscular DNA immunizations. J Immunol. 1997 May 15;158(10):4529–4532. [PubMed] [Google Scholar]
  63. Westwick J. K., Weitzel C., Minden A., Karin M., Brenner D. A. Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem. 1994 Oct 21;269(42):26396–26401. [PubMed] [Google Scholar]
  64. Yamamoto S., Yamamoto T., Kataoka T., Kuramoto E., Yano O., Tokunaga T. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity. J Immunol. 1992 Jun 15;148(12):4072–4076. [PubMed] [Google Scholar]
  65. Yi A. K., Tuetken R., Redford T., Waldschmidt M., Kirsch J., Krieg A. M. CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J Immunol. 1998 May 15;160(10):4755–4761. [PubMed] [Google Scholar]
  66. Yoshimori T., Yamamoto A., Moriyama Y., Futai M., Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem. 1991 Sep 15;266(26):17707–17712. [PubMed] [Google Scholar]
  67. Zal T., Volkmann A., Stockinger B. Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med. 1994 Dec 1;180(6):2089–2099. doi: 10.1084/jem.180.6.2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zimmermann S., Egeter O., Hausmann S., Lipford G. B., Röcken M., Wagner H., Heeg K. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J Immunol. 1998 Apr 15;160(8):3627–3630. [PubMed] [Google Scholar]
  69. van Dam H., Wilhelm D., Herr I., Steffen A., Herrlich P., Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995 Apr 18;14(8):1798–1811. doi: 10.1002/j.1460-2075.1995.tb07168.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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