Lipoxins as an Immune-Escape Mechanism

  • Fabiana S. Machado
  • Julio Aliberti
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 666)


Here, we discuss the mechanisms of repression of signaling pathways that are triggered by Lipoxin (LX) and are responsible for control of pro-inflammatory response during chronic phase of Toxoplasma gondii infection. We also discuss this mechanism from the perspective of the pathogen, which pirates the host s lipoxygenase machinery to its own advantage as a probable immune-escape mechanism. Pro-inflammatory mediators such as IL-12, IFN-y and TNF are essential in controlling parasite growth during T. gondii infection. However, it is clear that exacerbated production of these cytokines results in host tissue damage. LX, an anti-inflammatory eicosanoid, plays an important role in regulation of immune response to T. gondii.


Aryl Hydrocarbon Receptor Toxoplasma Gondii Toxoplasma Infection Aryl Hydrocarbon Receptor Nuclear Translocator Host Tissue Damage 
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  1. 1.
    Martinez AJ, Sell M, Mitrovics T et al. The neuropathology and epidemiology of AIDS. A Berlin experience. A review of 200 cases. Pathol Res Pract 1995; 191(5):427–443.PubMedGoogle Scholar
  2. 2.
    Morisaki JH, Heuser JE, Sibley LD. Invasion of Toxoplasma gondii occurs by active penetration of the host cell. J Cell Sci 1995; 108(Pt 6):2457–2464.PubMedGoogle Scholar
  3. 3.
    Black MW, Boothroyd JC. Lytic cycle of Toxoplasma gondii. Microbiol MolBiol Rev 2000; 64(3):607–623.CrossRefGoogle Scholar
  4. 4.
    Hay J, Hutchison WM. Toxoplasmagondii-Anenvironmental contaminant. Ecol Dis 1983; 2(1):33–43.PubMedGoogle Scholar
  5. 5.
    Serhan CN, Hamberg M, Samuelsson B. Lipoxins: Novel series of biologically active compounds formed from arachidonic acid in human leukocytes. ProcNatl Acad Sei USA 1984; 81(17):5335–5339.CrossRefGoogle Scholar
  6. 6.
    Aliberti J. Host persistence: exploitation of anti-inflammatory pathways by Toxoplasma gondii. Nat Rev Immunol 2005; 5(2):162–170.CrossRefPubMedGoogle Scholar
  7. 7.
    Funk CD, Chen XS, Johnson EN et al. Lipoxygenase genes and their targeted disruption. Prostaglandins Other Lipid Mediat 2002; 68–69:303–312.CrossRefPubMedGoogle Scholar
  8. 8.
    Fiore S, Romano M, Reardon EM et al. Induction of functional lipoxin A4 receptorsin HL-60 cells. Blood 1993; 81(12):3395–3403.PubMedGoogle Scholar
  9. 9.
    Fiore S, Maddox JF, Perez HD et al. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J Exp Med 1994; 180(1):253–260.CrossRefGoogle Scholar
  10. 10.
    Schaldach CM, Riby J, Bjeldanes LF. Lipoxin A4: A new class of ligand for the Ah receptor. Biochemistry 1999; 38(23):7594–7600.CrossRefPubMedGoogle Scholar
  11. 11.
    Mandai PK. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol [B] 2005; 175(4): 221–230.Google Scholar
  12. 12.
    Aliberti J, Hieny S, Reis e Sousa C et al. Lipoxin-mediated inhibition of IL-12 production by DCs: A mechanism for regulation of microbial immunity. Nat Immunol 2002; 3(1):76–82.CrossRefPubMedGoogle Scholar
  13. 13.
    Dannenberg GL, Aliberti J, Hong S et al. Exogenous pathogen and plant 15-lipoxygenase initiate endogenous lipoxin A4 biosynthesis. J Exp Med 2004; 199(4):515–523.CrossRefGoogle Scholar
  14. 14.
    Scharton-Kersten TM, Wynn TA, Denkers EY et al. In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii whilefailing to control acuteinfection. J Immunol 1996; 157 (9):4045–4054.Google Scholar
  15. 15.
    Liu CH, Fan YT, Dias A et al. Cutting Edge: Dendritic cells are essential forin vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. J Immunol 2006; 177(1):31–35.PubMedGoogle Scholar
  16. 16.
    Reis e Sousa C, Hieny S, Scharton-Kersten T et al. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T-cell areas. J Exp Med 1997; 186(11):1819–1829.CrossRefPubMedGoogle Scholar
  17. 17.
    Aliberti J, Reis e Sousa C, Schito M et al. CCR5 providesa signal for microbial induced production of IL-12 by CD8 α+ dendritic cells. Nat Immunol 2000; 1(1):83–87.CrossRefPubMedGoogle Scholar
  18. 18.
    Aliberti J, Valenzuela JG, Carruthers VB et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 2003; 4(5):485–490.CrossRefPubMedGoogle Scholar
  19. 19.
    Scanga CA, Aliberti J, Jankovic D et al. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. JImmunol 2002; 168(12):5997–6001.Google Scholar
  20. 20.
    Yarovinsky F, Zhang D, Andersen JF et al. TLR11activation of dendritic cells by a protozoan profilin-like protein. Science 2005; 308(5728): 1626–1629.CrossRefPubMedGoogle Scholar
  21. 21.
    Hunter CA, Chizzonite R, Remington JS. IL-1 beta is required for IL-12 to induce production of IFN-gamma by NK cells. A role for IL-1 beta in the T-cell-independent mechanism of resistance against intracellular pathogens. J Immunol 1995;155(9):4347–4354.PubMedGoogle Scholar
  22. 22.
    Sher A, Oswald IP, Hieny S et al. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha. J Immunol 1993; 150(9):3982–3989.PubMedGoogle Scholar
  23. 23.
    Yap GS, Sher A. Cell-mediated immunity to Toxoplasma gondii:Initiation, regulation and effector function. Immunobiology 1999; 201(2):240–247.PubMedGoogle Scholar
  24. 24.
    Karp CL, Wills-Karp M. Complement and IL-12: yin and yang. Microbes Infect 2001; 3(2):109–119.CrossRefPubMedGoogle Scholar
  25. 25.
    Son ES, Song KJ, Shin JC et al. Molecular cloning and characterization of peroxiredoxin from Toxo-plasma gondii. Korean J Parasitol 2001; 39(2):133–141.CrossRefPubMedGoogle Scholar
  26. 26.
    Leonard MO, Hannan K, Burne MJ et al. 15-Epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester, a synthetic analogue of 15-epi-lipoxin A(4), is protective in experimental ischemic acute renal failure. J Am Soc Nephrol 2002; 13(6):1657–1662.CrossRefPubMedGoogle Scholar
  27. 27.
    Kile BT, Schulman BA, Alexander WS et al. The SOCS box: A tale of destruction and degradation. Trends Biochem Sei 2002; 27(5):235–241.CrossRefGoogle Scholar
  28. 28.
    Alexander WS, Hilton DJ. The role of suppressors of cytokine signaling (SOCS) proteins inregulation of the immune response. Annu Rev Immunol 2004; 22:503–529.CrossRefPubMedGoogle Scholar
  29. 29.
    Starr R, Metealf D, Elefanty AG et al. Liver degeneration and lymphoid deficienciesin mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sei USA 1998; 95(24): 14395–14399.CrossRefGoogle Scholar
  30. 30.
    Marine JC, McKay C, Wang D et al. SOC S3 is essential in the regulation of fetal liver erythropoiesis. Cell 1999; 98(5):617–627.CrossRefPubMedGoogle Scholar
  31. 31.
    Metealf D, Greenhalgh CJ, Viney E et al. Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 2000; 405(6790):1069–1073.CrossRefGoogle Scholar
  32. 32.
    Kopchick JJ, Bellush LL, Coschigano KT. Transgenic models of growth hormoneaction. Annu Rev Nutr 1999; 19:437–461.CrossRefPubMedGoogle Scholar
  33. 33.
    Colao A, Merola B, Ferone D et al. Acromegaly. JClin Endocrinol Metab 1997; 82(9):2777–2781.CrossRefGoogle Scholar
  34. 34.
    Bradford GE, Famula TR. Evidence for a major gene for rapid postweaning growth in mice. Genet Res 1984; 44(3):293–308.CrossRefPubMedGoogle Scholar
  35. 35.
    Machado FS, Johndrow JE, Esper L et al. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. NatMed 2006; 12(3):330–334.Google Scholar
  36. 36.
    Hachicha M, Pouliot M, Petasis NA et al. Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor1 alpha-initiated neutrophil responsesand trafficking: Regulators of a cytokine-chemokine axis. J Exp Med 1999; 189(12): 1923–1930.CrossRefPubMedGoogle Scholar
  37. 37.
    Machado FS, Esper L, Dias A et al. Native and aspirin-triggered lipoxins controlinnate immunity by inducing proteasomal degradation of TRAF6. J Exp Med 2008; 205(5):1077–1086.CrossRefPubMedGoogle Scholar
  38. 38.
    Choi Y. Role of TRAF6 in the immune system. Adv Exp Med Biol 2005; 560:77–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Lomaga MA, Yeh WC, Sarosi I et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40 and LPS signaling. Genes Dev 1999; 13(8):1015–1024.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Division of Molecular ImmunologyCincinnati Children’s Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiUSA

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