Roles of Soluble and Membrane TNF and Related Ligands in Mycobacterial Infections: Effects of Selective and Non-selective TNF Inhibitors During Infection

  • Irene Garcia
  • Maria L. Olleros
  • Valerie F.J. Quesniaux
  • Muazzam Jacobs
  • Nasiema Allie
  • Sergei A. Nedospasov
  • David E. Szymkowski
  • Bernhard Ryffel
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


TNF plays an essential and non-redundant role in host defense mechanisms against Mycobacterium tuberculosis (Mtb) infection. TNF contributes to the development of granulomas, microstructures encasing pathogens and concentrating interactions between phagocytes and lymphocytes, and promotes bactericidal pathways to limit and destroy the invading intracellular pathogen. Production of TNF is associated with the development of human inflammatory diseases, and its inhibition, although an effective therapy, increases the risk of infections including either new or reactivation of tuberculosis infection. Studies on the role of membrane TNF in the absence of secreted TNF using genetic mouse models have shown that membrane TNF protects from M. bovis BCG and acute M. tuberculosis infections but does not induce inflammation in mouse. Pharmacological approaches of selective and non-selective soluble TNF inhibition show that a selective inhibitor of soluble TNF does not suppress host immunity to M. tuberculosis and M. bovis BCG infections, yet protects mice from arthritis and liver inflammatory diseases. This suggests that neutralization of soluble TNF may be effective to inhibit inflammatory diseases and also reduce the infection risks associated with current anti-TNF therapies.


Tuberculosis Infection Mycobacterial Infection Latent Tuberculosis Bactericidal Mechanism Genetic Mouse Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from EC (TB REACT Contract no. 028190) and FNRS (to IG).


  1. 1.
    Cegielski JP, McMurray DN (2004) The relationship between malnutrition and tuberculosis: evidence from studies in humans and experimental animals. Int J Tuberc Lung Dis 8:286–298PubMedGoogle Scholar
  2. 2.
    Schaible UE, Kaufmann SH (2007) Malnutrition and infection: complex mechanisms and global impacts. PLoS Med 4:e115CrossRefPubMedGoogle Scholar
  3. 3.
    Cardona PJ (2007) New insights on the nature of latent tuberculosis infection and its treatment. Inflamm Allergy Drug Targets 6:27–39CrossRefPubMedGoogle Scholar
  4. 4.
    Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098–1104CrossRefPubMedGoogle Scholar
  5. 5.
    Ehlers S (2003) Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF. Ann Rheum Dis 62 Suppl 2:ii37–42Google Scholar
  6. 6.
    Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H., Hua Y., Teoh LS, Fischkoff SA, Chartash EK (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400–1411CrossRefPubMedGoogle Scholar
  7. 7.
    Wallis RS, Broder M, Wong J, Beenhouwer D (2004) Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis 39:1254–1255CrossRefPubMedGoogle Scholar
  8. 8.
    Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO (2004) Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 38:1261–1265CrossRefPubMedGoogle Scholar
  9. 9.
    Kaufmann SH (2005) Recent findings in immunology give tuberculosis vaccines a new boost. Trends Immunol 26:660–667CrossRefPubMedGoogle Scholar
  10. 10.
    Flynn JL, Chan J (2001) Immunology of tuberculosis. Annu Rev Immunol 19:93–129CrossRefPubMedGoogle Scholar
  11. 11.
    Saunders BM, Britton WJ (2007) Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol 85:103–111CrossRefPubMedGoogle Scholar
  12. 12.
    Harris J, Master SS, De Haro SA, Delgado M., Roberts EA, Hope JC, Keane J, Deretic V (2009) Th1-Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages. Vet Immunol Immunopathol 128:37–43CrossRefPubMedGoogle Scholar
  13. 13.
    Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385:729–733CrossRefPubMedGoogle Scholar
  14. 14.
    Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385:733–736CrossRefPubMedGoogle Scholar
  15. 15.
    Garton KJ, Gough PJ, Raines EW (2006) Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J Leukoc Biol 79:1105–1116CrossRefPubMedGoogle Scholar
  16. 16.
    Ruddle NH (1999) Lymphoid neo-organogenesis: lymphotoxin’s role in inflammation and development. Immunol Res 19:119–125CrossRefPubMedGoogle Scholar
  17. 17.
    Alexopoulou L, Pasparakis M, Kollias G (1998) Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function. J Exp Med 188:745–754CrossRefPubMedGoogle Scholar
  18. 18.
    Endres R, Alimzhanov MB, Plitz T, Futterer A, Kosco-Vilbois MH, Nedospasov SA, Rajewsky K, Pfeffer K (1999) Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells. J Exp Med 189:159–168CrossRefPubMedGoogle Scholar
  19. 19.
    Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819CrossRefPubMedGoogle Scholar
  20. 20.
    Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O’Brine-Greco B, Foley SF, Ware CF (1993) Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72:847–856CrossRefPubMedGoogle Scholar
  21. 21.
    Elewaut D, Ware CF (2007) The unconventional role of LT alpha beta in T cell differentiation. Trends Immunol 28:169–175CrossRefPubMedGoogle Scholar
  22. 22.
    Tartaglia LA, Goeddel DV (1992) Two TNF receptors. Immunol Today 13:151–153CrossRefPubMedGoogle Scholar
  23. 23.
    Brouckaert P, Fiers W (1996) Tumor necrosis factor and the systemic inflammatory response syndrome. Curr Top Microbiol Immunol 216:167–187PubMedGoogle Scholar
  24. 24.
    Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8:21–30CrossRefPubMedGoogle Scholar
  25. 25.
    Abe K, Yarovinsky FO, Murakami T, Shakhov AN, Tumanov AV, Ito D, Drutskaya LN, Pfeffer K, Kuprash DV, Komschlies KL, Nedospasov SA (2003) Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Blood 101:1477–1483CrossRefPubMedGoogle Scholar
  26. 26.
    Murphy KM, Nelson CA, Sedy JR (2006) Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 6:671–681CrossRefPubMedGoogle Scholar
  27. 27.
    Scheu S, Alferink J, Potzel T, Barchet W, Kalinke U, Pfeffer K (2002) Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J Exp Med 195:1613–1624CrossRefPubMedGoogle Scholar
  28. 28.
    Jacobs M, Togbe D, Fremond C, Samarina A, Allie N, Botha T, Carlos D, Parida SK, Grivennikov S, Nedospasov S, Monteiro A, Le Bert M, Quesniaux V, Ryffel B (2007) Tumor necrosis factor is critical to control tuberculosis infection. Microbes Infect 9:623–628CrossRefPubMedGoogle Scholar
  29. 29.
    Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P (1989) The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56:731–740CrossRefPubMedGoogle Scholar
  30. 30.
    Garcia I, Miyazaki Y, Marchal G, Lesslauer W, Vassalli P (1997) High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: synergistic action of TNF and IFN-gamma in the differentiation of protective granulomas. Eur J Immunol 27:3182–3190CrossRefPubMedGoogle Scholar
  31. 31.
    Guler R, Olleros ML, Vesin D, Parapanov R, Garcia I (2005) Differential effects of total and partial neutralization of tumor necrosis factor on cell-mediated immunity to Mycobacterium bovis BCG infection. Infect Immun 73:3668–3676CrossRefPubMedGoogle Scholar
  32. 32.
    Jacobs M, Brown N, Allie N, Ryffel B (2000) Fatal Mycobacterium bovis BCG infection in TNF-LT-alpha-deficient mice. Clin Immunol 94:192–199CrossRefPubMedGoogle Scholar
  33. 33.
    Bopst M, Garcia I, Guler R, Olleros ML, Rulicke T, Muller M, Wyss S, Frei K, M Le Hir, Eugster HP (2001) Differential effects of TNF and LTalpha in the host defense against M. bovis BC. Eur G. J Immunol 31:1935–1943Google Scholar
  34. 34.
    Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, Schreiber R, Mak TW, Bloom BR (1995) Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561–572CrossRefPubMedGoogle Scholar
  35. 35.
    Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD, Britton WJ (1999) Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 162:3504–3511PubMedGoogle Scholar
  36. 36.
    Kaneko H, Yamada H, Mizuno S, Udagawa T, Kazumi Y, Sekikawa K, Sugawara I (1999) Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice. Lab Invest 79:379–386PubMedGoogle Scholar
  37. 37.
    Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ (2002) TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 168:4620–4627PubMedGoogle Scholar
  38. 38.
    Adams LB, Mason CM, Kolls JK, Scollard D, Krahenbuhl JL, Nelson S (1995) Exacerbation of acute and chronic murine tuberculosis by administration of a tumor necrosis factor receptor-expressing adenovirus. J Infect Dis 171:400–405PubMedGoogle Scholar
  39. 39.
    Smith S, Liggitt D, Jeromsky E, Tan X, Skerrett SJ, Wilson CB (2002) Local role for tumor necrosis factor alpha in the pulmonary inflammatory response to Mycobacterium tuberculosis infection. Infect Immun 70:2082–2089CrossRefPubMedGoogle Scholar
  40. 40.
    Zganiacz A, Santosuosso M, Wang J, Yang T, Chen L, Anzulovic M, Alexander S, Gicquel B, Wan Y, Bramson J, Inman M, Xing Z (2004) TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection. J Clin Invest 113:401–413PubMedGoogle Scholar
  41. 41.
    Plessner HL, Lin PL, Kohno T, Louie JS, Kirschner D, Chan J, Flynn JL (2007) Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis. J Infect Dis 195:1643–1650CrossRefPubMedGoogle Scholar
  42. 42.
    Botha T, Ryffel B (2003) Reactivation of latent tuberculosis infection in TNF-deficient mice. J Immunol 171:3110–3118PubMedGoogle Scholar
  43. 43.
    Senaldi G, Yin S, Shaklee CL, Piguet PF, Mak TW, Ulich TR (1996) Corynebacterium parvum- and Mycobacterium bovis bacillus Calmette-Guerin-induced granuloma formation is inhibited in TNF receptor I (TNF-RI) knockout mice and by treatment with soluble TNF-RI. J Immunol 157:5022–5026PubMedGoogle Scholar
  44. 44.
    Ehlers S, Benini J, Kutsch S, Endres R, Rietschel ET, Pfeffer K (1999) Fatal granuloma necrosis without exacerbated mycobacterial growth in tumor necrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium. Infect Immun 67:3571–3579PubMedGoogle Scholar
  45. 45.
    Jacobs M, Brown N, Allie N, Chetty K, Ryffel B (2000) Tumor necrosis factor receptor 2 plays a minor role for mycobacterial immunity. Pathobiology 68:68–75CrossRefPubMedGoogle Scholar
  46. 46.
    Egen JG, Rothfuchs AG, Feng CG, Winter N, Sher A, Germain RN (2008) Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28:271–284CrossRefPubMedGoogle Scholar
  47. 47.
    Clay H, Volkman HE, Ramakrishnan L (2008) Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity 29:283–294CrossRefPubMedGoogle Scholar
  48. 48.
    Decker T, Lohmann-Matthes ML, Gifford GE (1987) Cell-associated tumor necrosis factor (TNF) as a killing mechanism of activated cytotoxic macrophages. J Immunol 138:957–962PubMedGoogle Scholar
  49. 49.
    Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K, Scheurich P (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793–802CrossRefPubMedGoogle Scholar
  50. 50.
    Haas E, Grell M, Wajant H, Scheurich P (1999) Continuous autotropic signaling by membrane-expressed tumor necrosis factor. J Biol Chem 274:18107–18112CrossRefPubMedGoogle Scholar
  51. 51.
    Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184:1397–1411CrossRefPubMedGoogle Scholar
  52. 52.
    Mueller C, Corazza N, Trachsel-Loseth S, Eugster HP, Buhler-Jungo M, Brunner T, Imboden MA (1999) Noncleavable transmembrane mouse tumor necrosis factor-alpha (TNFalpha) mediates effects distinct from those of wild-type TNFalpha in vitro and in vivo. J Biol Chem 274:38112–38118CrossRefPubMedGoogle Scholar
  53. 53.
    Akassoglou K, Probert L, Kontogeorgos G, Kollias G (1997) Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J Immunol 158:438–445PubMedGoogle Scholar
  54. 54.
    Ruuls SR, Hoek RM, Ngo VN, McNeil T, Lucian LA, Janatpour MJ, Korner H, Scheerens H, Hessel EM, Cyster JG, McEvoy LM, Sedgwick JD (2001) Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. Immunity 15:533–543CrossRefPubMedGoogle Scholar
  55. 55.
    Eissner G, Kolch W, Scheurich P (2004) Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev 15:353–366CrossRefPubMedGoogle Scholar
  56. 56.
    Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD, Chaudhri G (1999) A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in ’reverse signalling’. EMBO J 18:2119–2126CrossRefPubMedGoogle Scholar
  57. 57.
    Kirchner S, Boldt S, Kolch W, Haffner S, Kazak S, Janosch P, Holler E, Andreesen R, Eissner G (2004) LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway. J Leukoc Biol 75:324–331CrossRefPubMedGoogle Scholar
  58. 58.
    Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, Otsuka J, Okamura S, Fujita S, Harada M (2005) Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 128:376–392CrossRefPubMedGoogle Scholar
  59. 59.
    Olleros ML, Guler R, Corazza N, Vesin D, Eugster HP, Marchal G, Chavarot P, Mueller C, Garcia I (2002) Transmembrane TNF induces an efficient cell-mediated immunity and resistance to Mycobacterium bovis bacillus Calmette-Guerin infection in the absence of secreted TNF and lymphotoxin-alpha. J Immunol 168:3394–3401PubMedGoogle Scholar
  60. 60.
    Olleros ML, Guler R, Vesin D, Parapanov R, Marchal G, Martinez-Soria E, Corazza N, Pache JC, Mueller C, Garcia I (2005) Contribution of transmembrane tumor necrosis factor to host defense against Mycobacterium bovis bacillus Calmette-guerin and Mycobacterium tuberculosis infections. Am J Pathol 166:1109–1120PubMedGoogle Scholar
  61. 61.
    Saunders BM, Tran S, Ruuls S, Sedgwick JD, Briscoe H, Britton WJ (2005) Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of Mycobacterium tuberculosis infection. J Immunol 174:4852–4859PubMedGoogle Scholar
  62. 62.
    Fremond C, Allie N, Dambuza I, Grivennikov SI, Yeremeev V, Quesniaux VF, Jacobs M, Ryffel B (2005) Membrane TNF confers protection to acute mycobacterial infection. Respir Res 6:136CrossRefPubMedGoogle Scholar
  63. 63.
    Allie N, Alexopoulou L, Quesniaux VJ, Fick L, Kranidioti K, Kollias G, Ryffel B, Jacobs M (2008) Protective role of membrane tumour necrosis factor in the host’s resistance to mycobacterial infection. Immunology 125:522–534Google Scholar
  64. 64.
    Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ (2001) Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J Exp Med 193:239–246CrossRefPubMedGoogle Scholar
  65. 65.
    Liepinsh DJ, Grivennikov SI, Klarmann KD, Lagarkova MA, Drutskaya MS, Lockett SJ, Tessarollo L, McAuliffe M, Keller JR, Kuprash DV, Nedospasov SA (2006) Novel lymphotoxin alpha (LTalpha) knockout mice with unperturbed tumor necrosis factor expression: reassessing LTalpha biological functions. Mol Cell Biol 26:4214–4225CrossRefPubMedGoogle Scholar
  66. 66.
    Lucas R, Tacchini-Cottier F, Guler R, Vesin D, Jemelin S, Olleros ML, Marchal G, Browning JL, Vassalli P, Garcia I (1999) A role for lymphotoxin beta receptor in host defense against Mycobacterium bovis BCG infection. Eur J Immunol 29:4002–4010CrossRefPubMedGoogle Scholar
  67. 67.
    Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70CrossRefPubMedGoogle Scholar
  68. 68.
    Ehlers S, Holscher C, Scheu S, Tertilt C, Hehlgans T, Suwinski J, Endres R, Pfeffer K (2003) The lymphotoxin beta receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J Immunol 170:5210–5218PubMedGoogle Scholar
  69. 69.
    Desai SB, Furst DE (2006) Problems encountered during anti-tumour necrosis factor therapy. Best Pract Res Clin Rheumatol 20:757–790CrossRefPubMedGoogle Scholar
  70. 70.
    Hamdi H, Mariette X, Godot V, Weldingh K, Hamid AM, Prejean MV, Baron G, Lemann M, Puechal X, Breban M, Berenbaum F, Delchier JC, Flipo RM, Dautzenberg B, Salmon D, Humbert M, Emilie D (2006) Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists. Arthritis Res Ther 8:R114CrossRefPubMedGoogle Scholar
  71. 71.
    Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, Miller CH, Dutcher PO, Hadley JA, Sanz I (2008) Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks. J Immunol 180:688–692PubMedGoogle Scholar
  72. 72.
    Bruns H, Meinken C, Schauenberg P, Harter G, Kern P, Modlin RL, Antoni C, Stenger S (2009) Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans. J Clin Invest 119:1167–1177CrossRefPubMedGoogle Scholar
  73. 73.
    Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O’Brien C, O’Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI (2003) Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 301:1895–1898CrossRefPubMedGoogle Scholar
  74. 74.
    Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O’Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, Szymkowski DE (2007) Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol 179:1872–1883PubMedGoogle Scholar
  75. 75.
    McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26:9365–9375CrossRefPubMedGoogle Scholar
  76. 76.
    Olleros ML, Vesin D, Lambou AF, Janssens J.-P, Ryffel B, Rose S, Frémond C, Quesniaux VF, Szymkowski DE, Garcia I (2009) Dominant-Negative TNF Protects from Mycobacterium bovis BCG and Endotoxin-Induced Liver Injury Without Compromising Host Immunity to BCG and M. tuberculosis. J Infectious Diseases 199:1053–1063Google Scholar
  77. 77.
    Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117:244–279CrossRefPubMedGoogle Scholar
  78. 78.
    Spohn G, Guler R, Johansen P, Keller I, Jacobs M, Beck M, Rohner F, Bauer M, Dietmeier K, Kundig TM, Jennings GT, Brombacher F, Bachmann MF (2007) A virus-like particle-based vaccine selectively targeting soluble TNF-alpha protects from arthritis without inducing reactivation of latent tuberculosis. J Immunol 178:7450–7457PubMedGoogle Scholar
  79. 79.
    Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ (2000) A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288:2351–2354CrossRefPubMedGoogle Scholar
  80. 80.
    Deng GM, Zheng L, Chan FK, Lenardo M (2005) Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat Med 11:1066–1072CrossRefPubMedGoogle Scholar
  81. 81.
    Serrano-Vega MJ, Magnani F, Shibata Y, Tate CG (2008) Conformational thermostabilization of the beta1-adrenergic receptor in a detergent-resistant form. Proc Natl Acad Sci U S A 105:877–882CrossRefPubMedGoogle Scholar
  82. 82.
    Shibata H, Yoshioka Y, Ohkawa A, Abe Y, Nomura T, Mukai Y, Nakagawa S, Taniai M, Ohta T, Mayumi T, Kamada H, Tsunoda S, Tsutsumi Y (2008) The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models. Cytokine 44:229–233CrossRefPubMedGoogle Scholar
  83. 83.
    Shibata H, Yoshioka Y, Ohkawa A, Minowa K, Mukai Y, Abe Y, Taniai M, Nomura T, Kayamuro H, Nabeshi H, Sugita T, Imai S, Nagano K, Yoshikawa T, Fujita T, Nakagawa S, Yamamoto A, Ohta T, Hayakawa T, Mayumi T, Vandenabeele P, Aggarwal BB, Nakamura T, Yamagata Y, Tsunoda S, Kamada H, Tsutsumi Y (2008) Creation and X-ray structure analysis of the tumor necrosis factor receptor-1-selective mutant of a tumor necrosis factor-alpha antagonist. J Biol Chem 283:998–1007CrossRefPubMedGoogle Scholar
  84. 84.
    He MM, Smith AS, Oslob JD, Flanagan WM, Braisted AC, Whitty A, Cancilla MT, Wang J, Lugovskoy AA, Yoburn JC, Fung AD, Farrington G, Eldredge JK, Day ES, Cruz LA, Cachero TG, Miller SK, Friedman JE, Choong IC, Cunningham BC (2005) Small-molecule inhibition of TNF-alpha. Science 310:1022–1025CrossRefPubMedGoogle Scholar
  85. 85.
    Rhoades ER, Cooper AM, Orme IM (1995) Chemokine response in mice infected with Mycobacterium tuberculosis. Infect Immun 63:3871–3877PubMedGoogle Scholar
  86. 86.
    Peters W, Ernst JD (2003) Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Microbes Infect 5:151–158CrossRefPubMedGoogle Scholar
  87. 87.
    Algood HM, Lin PL, Flynn JL (2005) Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 41 Suppl 3:S189–193CrossRefGoogle Scholar
  88. 88.
    Seiler P, Aichele P, Bandermann S, Hauser AE, Lu B, Gerard NP, Gerard C, Ehlers S, Mollenkopf HJ, Kaufmann SH (2003) Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur J Immunol 33:2676–2686CrossRefPubMedGoogle Scholar
  89. 89.
    Freeman S, Post FA, Bekker LG, Harbacheuski R, Steyn LM, Ryffel B, Connell ND, Kreiswirth BN, Kaplan G (2006) Mycobacterium tuberculosis H37Ra and H37Rv differential growth and cytokine/chemokine induction in murine macrophages in vitro. J Interferon Cytokine Res 26:27–33CrossRefPubMedGoogle Scholar
  90. 90.
    Peters W, Scott HM, Chambers HF, Flynn JL, Charo IF, Ernst JD (2001) Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 98:7958–7963CrossRefPubMedGoogle Scholar
  91. 91.
    Algood HM, Flynn JL (2004) CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J Immunol 173:3287–3296PubMedGoogle Scholar
  92. 92.
    Chakravarty SD, Xu J, Lu B, Gerard C, Flynn J, Chan J (2007) The chemokine receptor CXCR3 attenuates the control of chronic Mycobacterium tuberculosis infection in BALB/c mice. J Immunol 178:1723–1735PubMedGoogle Scholar
  93. 93.
    Algood HM, Chan J, Flynn JL (2003) Chemokines and tuberculosis. Cytokine Growth Factor Rev 14:467–477CrossRefPubMedGoogle Scholar
  94. 94.
    MacEwan DJ (2002) TNF ligands and receptors--a matter of life and death. Br J Pharmacol 135:855–875CrossRefPubMedGoogle Scholar
  95. 95.
    MacEwan DJ (2002) TNF receptor subtype signalling: differences and cellular consequences. Cell Signal 14:477–492CrossRefPubMedGoogle Scholar
  96. 96.
    Grivennikov SI, Kuprash DV, Liu ZG, Nedospasov SA (2006) Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms. Int Rev Cytol 252:129–161CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Irene Garcia
    • 1
  • Maria L. Olleros
    • 1
  • Valerie F.J. Quesniaux
    • 2
  • Muazzam Jacobs
    • 3
  • Nasiema Allie
    • 3
  • Sergei A. Nedospasov
    • 4
    • 5
  • David E. Szymkowski
    • 6
  • Bernhard Ryffel
    • 7
  1. 1.Department of Pathology and ImmunologyCMU, University of GenevaGenevaSwitzerland
  2. 2.Orleans University and CNRS, Molecular Immunology and Embryology UMR6218OrleansFrance
  3. 3.Institute of Infectious Disease and Molecular Medicine, and National Health Laboratory ServiceUniversity of Cape TownCape TownSouth Africa
  4. 4.Laboratory of Molecular ImmunologyEngelhardt Institute of Molecular Biology, Russian Academy of SciencesMoscowRussia
  5. 5.German Rheumatism Research CenterBerlinGermany
  6. 6.Biotherapeutics Xencor, Inc.MonroviaUSA
  7. 7.Orleans University and CNRS, Molecular Immunology and EmbryologyOrleansFrance

Personalised recommendations