Immunologic Research

, Volume 23, Issue 2–3, pp 99–109 | Cite as

Innate immunity and inflammation: A transcriptional paradigm

Abstract

The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or super antigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proin flammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and super antigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-κB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-κB allow stranscriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-κB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-κB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFα and interferon γ) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation of cytokine genes that are controlled by NF-κB and other SRTFs.

Key Words

Innate Immunity Inflammation NF-κB Transcription Factors Monocytes and Macrophages T cells Nuclear Import Cell-Permeable Peptides Lipopolysaccharides Superantigens 

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References

  1. 1.
    Rosenberg HF, Gallin JI: Inflammation. Philadelphia, Lippincott-Raven Publishers, Fourth ed, 1999.Google Scholar
  2. 2.
    Pahl HL: Activators and target genes of Rel/Nf-kappaB transcription factors. Oncogene 1999; 18:6853–6866.PubMedCrossRefGoogle Scholar
  3. 3.
    Lefer DJ, Flynn DM, Phillips ML, Ratcliffe M, Buda AJ: A novel sialy 1 Lew is X analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion. Circulation 1994; 90:2390–2401.PubMedGoogle Scholar
  4. 4.
    Inauen W, Suzuki M, Granger DN: Mechanisms of cellular injury: potential sources of oxygen free radicals in ischemia/reperfusion. Microcirc Endothelium Lymphatics 1989;5:143–155.PubMedGoogle Scholar
  5. 5.
    Fowler AA, Hyers TM, Fisher BJ, Bechard DE, Centor RM, Webster RO: The adult respiratory distress syndrome. Cell populations and soluble mediators in the air spaces of patients at high risk. Am Rev Respir Dis 1987;136:1225–1231.PubMedGoogle Scholar
  6. 6.
    Lu YT, Hellewell PG, Evans TW: Ischemia-reperfusion lung injury: contribution of ischemia, neutrophils, and hydrostatic pressure. Am J Physiol 1997;273:L46-L54.PubMedGoogle Scholar
  7. 7.
    Matute-Bello G, Liles WC, Radella F 2nd, et al., Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 2000; 28:1–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Martin TR, Galli SJ, Katona IM, Drazen JM: Role of mast cells in an aphylaxis. Evidence for the importance of mast cells in the cardio pulmonary alterations and death induced by anti-IgE in mice. J Clin Invest 1989:83:1375–1383.PubMedGoogle Scholar
  9. 9.
    Gordon S 1999. Macrophages and the Immune Response, p. 533–545. In W. E. Paul (ed.) Fundamental Immunology, 4th ed., Lippincott-Raven, Philadelphia.Google Scholar
  10. 10.
    Lamhamedi S, Jouanguy E, Altare F, Roesler J, Casanova JL: Interferon-gamma receptor deficiency: relationship between genotype, environment, and phenotype (Review). Int J Mol Med 1998 1:415–418.PubMedGoogle Scholar
  11. 11.
    Car BD, Eng VM, Schnyder B, et al.: Interferon gamma receptor deficient mice are resistant to endotoxic shock. J Exp Med 1994;179: 1437–1444.PubMedCrossRefGoogle Scholar
  12. 12.
    Springer TA: Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76: 301–314.PubMedCrossRefGoogle Scholar
  13. 13.
    McEver RP, Cummings RD: Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 1997;100:S97-S103.PubMedGoogle Scholar
  14. 14.
    Yang J, Furie BC, Furie B: The biology of P-selectin glycoprotein ligand-1: its role as a select in counterreceptor in leukocy teendothelial and leukocyte-platelet interaction. Thromb Haemost 1999;81:1–7.PubMedGoogle Scholar
  15. 15.
    Anderson DC, Springer TA: Leukocyte adhesion deficiency: An inherited defect in the Mac-1, LFA-1, and P150,95 glycoproteins. Annu Rev Med 1987;38:175–194.PubMedCrossRefGoogle Scholar
  16. 16.
    Mizgerd JP, Kubo H, Kutkoski GJ, et al.: Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice. J Exp Med 1997; 186:1357–1364.PubMedCrossRefGoogle Scholar
  17. 17.
    Scharffetter-Kochanek K, Lu H, Norman K, et al.: Spontaneous skin ulceration and defective T cell function in CD 18 null mice. J Exp Med 1998;188:119–131.PubMedCrossRefGoogle Scholar
  18. 18.
    Frenette PS, Mayadas TN, Rayburn H, Hynes RO, Wagner DD: Susceptibility to infection and altered hemato poiesis in mice deficient in both P-and E-selectins. Cell 1996;84:563–574.PubMedCrossRefGoogle Scholar
  19. 19.
    Sligh JE Jr., Ballantyne CM, Rich SS, et al.: Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc. Natl Acad Sci USA 1993;90:8529–8533.PubMedCrossRefGoogle Scholar
  20. 20.
    Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T: Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995;9:899–909.PubMedGoogle Scholar
  21. 21.
    May MJ, D'Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S: Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB: kinase complex. Science 2000;289:1550–1554.PubMedCrossRefGoogle Scholar
  22. 22.
    Ulevitch RJ, Tobias PS: Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol 1995;13:437–457.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldfeld AE, McCaffrey PG, Strominger JL, Rao A: Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter. J Exp Med 1993;178:1365–1379.PubMedCrossRefGoogle Scholar
  24. 24.
    Cordle SR, Donald R, Read MA, Hawiger J: Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. J Biol Chem 1993;268:11,803–11,810.Google Scholar
  25. 25.
    Mackman N: Regulation of the tissue factor gene. FASEB J 1995; 9:883–889.PubMedGoogle Scholar
  26. 26.
    Liu XY, Robinson D, Veach RA, et al.: Peptide-Directed Suppression of a Pro-inflammatory Cytokine Response. J Biol Chem 2000; 275:16,774–16,778.Google Scholar
  27. 27.
    Medzhitov R, Janeway CA, Jr.: Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 1997;9:4–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF: A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998;95:588–593.PubMedCrossRefGoogle Scholar
  29. 29.
    Cao Z, Henzel WJ, Gao X: IRAK: a kinase associated with the interleukin-1 receptor. Science 1996; 271:1128–1131.PubMedCrossRefGoogle Scholar
  30. 30.
    Muzio M, Ni J, Feng P, Dixit VM: IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 1997;278:1612–1615.PubMedCrossRefGoogle Scholar
  31. 31.
    Medzhitov R, Preston-Hurlburt P, Kopp E, et al.: MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998;2:253–258.PubMedCrossRefGoogle Scholar
  32. 32.
    Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z: MyD88: an adapter that recruits IRAK to the IL-1 receptorcomplex. Immunity 1997; 7:837–847.PubMedCrossRefGoogle Scholar
  33. 33.
    Poltorak A, He X, Smirnova I, et al.: Defective LPS signaling in C3H/HeJ and C57BL/10 ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085–2088.PubMedCrossRefGoogle Scholar
  34. 34.
    Kawai T, Adachi O, Ogawa T, Takeda K, Akira S: Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999;11:115–122.PubMedCrossRefGoogle Scholar
  35. 35.
    Liebermann DA, Hoffman B: MyD genes in negative growth control. Oncogene 1998;17:3319–3329.PubMedCrossRefGoogle Scholar
  36. 36.
    Baldwin AS, Jr.: The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996;14:649–683.PubMedCrossRefGoogle Scholar
  37. 37.
    Donald R, Ballard DW, Hawiger J: Proteolytic processing of NF-kappa B/I kappa B in human monocytes ATP-dependent induction by pro-inflammatory mediators. J Biol Chem 1995;270:9–12.PubMedCrossRefGoogle Scholar
  38. 38.
    O'Connell MA, Bennett BL, Mercurio F, Manning AM, Mackman N: Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. J Biol Chem 1998;273:30,410–30,414.Google Scholar
  39. 39.
    Hawiger J, Veach RA, Liu XY, Timmons S, Ballard DW: IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Blood 1999;94:1711–1716.PubMedGoogle Scholar
  40. 40.
    Yang RB, Mark MR, Gray A, et al.: Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 1998;395:284–288.PubMedCrossRefGoogle Scholar
  41. 41.
    Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M: Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med 1998;188:2091–2097.PubMedCrossRefGoogle Scholar
  42. 42.
    Tsytsykova AV, Goldfeld AE: Nuclear Factor of Activated T Cells Transcription Factor NFATp Controls Superantigen-induced Lethal Shock.J Exp Med 2000;192:581–586.PubMedCrossRefGoogle Scholar
  43. 43.
    Gorlich D, Kutay U: Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 1999;15:607–660.PubMedCrossRefGoogle Scholar
  44. 44.
    Bohrer H, Qiu F, Zimmermamm T, et al.: Role of NFkappaB in the mortality of sepsis. J Clin Invest 1997;100:972–985.PubMedCrossRefGoogle Scholar
  45. 45.
    Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J: Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem 1995;270:14,255–14,258.Google Scholar
  46. 46.
    Hawiger J: Cellular import of functional peptides to block intracellular signaling. Curr Opin Immunol 1997;9:189–194.PubMedCrossRefGoogle Scholar
  47. 47.
    Hawiger J: Noninvasive intracellular delivery of functional peptidesand proteins. Curr Opin Chem Biol 1999;3:89–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Torgerson TR, Colosia AD, Donahue JP, Lin YZ, Hawiger J: Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50. J Immunol 1998;161:6084–6092.PubMedGoogle Scholar
  49. 49.
    Liu X-Y, Timmons S, Lin Y-Z, Hawiger J: Identification of a functionally important sequence in the cytoplasmic tail of integrin beta3 by using cell-permeable peptide analogs. Proc Natl Acad Sci USA 1996;93:11,819–11,824.Google Scholar
  50. 50.
    Tracey KJ, Fong Y, Hesse DG, et al.: Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–664.PubMedCrossRefGoogle Scholar
  51. 51.
    Michie HR, Manogue KR, Spriggs DR, et al.: Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988;318:1481–1486.PubMedCrossRefGoogle Scholar
  52. 52.
    Richardson RP, Rhyne CD, Fong Y, et al.: Peripheral blood leukocyte kinetics following in vivo lipopolysaccharide (LPS) administration to normal human subjects. Influence of elicited hormones and cytokines.Ann Surg 1989;210:239–245.PubMedCrossRefGoogle Scholar
  53. 53.
    RemickDG, Strieter RM, Eskandari MK, et al.: Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations. Am J Pathol 1990;136:49–60.PubMedGoogle Scholar
  54. 54.
    van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A: Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990;76:2520–2526.PubMedGoogle Scholar
  55. 55.
    Alexander HR, Doherty GM, Buresh CM, Venzon DJ, Norton JA: A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 1991;173:1029–1032.PubMedCrossRefGoogle Scholar
  56. 56.
    Amiot F, Fitting C, Tracey KJ, Cavaillon JM, Dautry F: Lipopolysaccharide-induced cytokine casade and lethality in LT alpha/TNF alpha-deficient mice. Mol Med 1997;3:864–875.PubMedGoogle Scholar
  57. 57.
    Fujihara SM, Cleaveland JS, Grosmaire LS, et al.: A D-amino acid peptide inhibitor of NF-kappa B nuclear localization is efficacious in models of inflammatory disease. J Immunol 2000;165:1004–1012.PubMedGoogle Scholar
  58. 58.
    Scherer MT, Ignatowicz L, Winslow GM, Kappler JW, Marrack P: Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol 1993;9:101–128.PubMedCrossRefGoogle Scholar
  59. 59.
    Schlievert PM: Will therapeutic peptides be kryptonite for superantigens? Nat Med 2000;6:378–379.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyVanderbilt University School of MedicineNashville

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