Heme Sensitization to TNF-Mediated Programmed Cell Death

  • Raffaella Gozzelino
  • Miguel P. Soares
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


The cytotoxic effect of tumor necrosis factor (TNF) is repressed in most cell types through the expression of several immediate–early TNF-responsive cytoprotective genes. To the best of our knowledge, there are no molecules produced under pathophysiologic condition that have been shown to override this cytoprotective effect. Identification of such molecules should contribute to our current understanding of the mechanisms underlying the pathophysiologic effects of TNF. We will argue that free heme acts in such a manner, promoting TNF-driven cytotoxicity, which might be an important component of the pathogenesis of several immune-mediated inflammatory diseases, as illustrated hereby for malaria.


Tumor Necrosis Factor Programme Cell Death Severe Malaria Cerebral Malaria Blood Stage 
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.





Jun N-terminal kinase


nuclear factor kappa B



The authors thank Rasmus Larsen for invaluable help in producing the figure of this chapter as well as all members of the inflammation laboratory for critical input in the ideas and data that support the models put forward in this manuscript. This work was supported in part by “Fundação para a Ciência e Tecnologia,” Portugal grants SFRH/BPD/44256/2008 to RG, POCTI/SAU-MNO/56066/2004 and PTDC/SAU-MII/65765/2006 to MPS. Support was also provided by European Community grants, 6th Framework Xenome (LSH-2005-1.2.5-1), and by the Gemi Fund (Linde Healthcare) to MPS.


  1. 1.
    Gozzelino R, Jeney V, Soares M (2010) Mechanisms of cell protection by heme oxygnease-1. Ann Rev Pharmacol Toxicol 50:323–354Google Scholar
  2. 2.
    Furuyama K, Kaneko K, Vargas PD (2007) Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis. Tohoku J Exp Med 213:1–16CrossRefPubMedGoogle Scholar
  3. 3.
    Tsiftsoglou AS, Tsamadou AI, Papadopoulou LC (2006) Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects. Pharmacol Ther 111:327–345CrossRefPubMedGoogle Scholar
  4. 4.
    Mustafa AK, Gadalla MM, Snyder SH (2009) Signaling by gasotransmitters. Sci Signal 2:re2CrossRefPubMedGoogle Scholar
  5. 5.
    Fenton HJH (1894) Oxidation of tartaric acid in presence of iron. Journal of the Chemical society (Lond.) 65Google Scholar
  6. 6.
    Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM (1992) Ferritin: a cytoprotective antioxidant strategem of endothelium. Journal of Biological Chemistry 267:18148–18153PubMedGoogle Scholar
  7. 7.
    Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, Balla G (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood 100:879–887CrossRefPubMedGoogle Scholar
  8. 8.
    Soares MP, Bach FH (2009) Heme oxygenase-1: from biology to therapeutic potential. Trends Mol Med 15:50–58CrossRefPubMedGoogle Scholar
  9. 9.
    Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 86:1097–1111CrossRefPubMedGoogle Scholar
  10. 10.
    Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A, Soares MP (2009) Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci U S A 106:15837–15842CrossRefPubMedGoogle Scholar
  11. 11.
    Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434:214–217CrossRefPubMedGoogle Scholar
  12. 12.
    Miller LH, Baruch DI, Marsh K, Doumbo OK (2002) The pathogenic basis of malaria. Nature 415:673–679CrossRefPubMedGoogle Scholar
  13. 13.
    Mota MM, Pradel G, Vanderberg JP, Hafalla JC, Frevert U, Nussenzweig RS, Nussenzweig V, Rodriguez A (2001) Migration of Plasmodium sporozoites through cells before infection. Science 291:141–144CrossRefPubMedGoogle Scholar
  14. 14.
    Prudencio M, Rodriguez A, Mota MM (2006) The silent path to thousands of merozoites: the Plasmodium liver stage. Nat Rev Microbiol 4:849–856CrossRefPubMedGoogle Scholar
  15. 15.
    Bach FH, Hancock WW, Ferran C (1997) Protective genes expressed in endothelial cells – a regulatory response to injury. Immunology Today 18:483–486CrossRefPubMedGoogle Scholar
  16. 16.
    Epiphanio S, Albuquerque S, Soares S, Mota MM (2005) The role of HO-1 and CO in Malaria Hepatic Stage. In ELSO Meeting. Dresden, GermanyGoogle Scholar
  17. 17.
    WHO (2000) Expert Committee on Malaria: 20th Report.
  18. 18.
    Idro R, Jenkins NE, Newton CR (2005) Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 4:827–840CrossRefPubMedGoogle Scholar
  19. 19.
    Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N et al (1995) Indicators of life-threatening malaria in African children. N Engl J Med 332:1399–1404CrossRefPubMedGoogle Scholar
  20. 20.
    Maitland K, Marsh K (2004) Pathophysiology of severe malaria in children. Acta Trop 90:131–140CrossRefPubMedGoogle Scholar
  21. 21.
    Francis SE, Sullivan DJ Jr, Goldberg DE (1997) Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Microbiol 51:97–123CrossRefPubMedGoogle Scholar
  22. 22.
    Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature. 409:198–201CrossRefPubMedGoogle Scholar
  23. 23.
    Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha-Rodrigues M, Portugal S, Soares MP, Mota MM (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13:703–710CrossRefPubMedGoogle Scholar
  24. 24.
    Rother RP, Bell L, Hillmen P, Gladwin MT. 2005. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. Jama 293:1653–1662CrossRefPubMedGoogle Scholar
  25. 25.
    Uko EK, Udoh AE, Etukudoh MH (2003) Methaemoglobin profile in malaria infected children in Calabar. Niger J Med 12:94–97PubMedGoogle Scholar
  26. 26.
    Bunn HF, Jandl JH (1966) Exchange of heme among hemoglobin molecules. Proc Natl Acad Sci U S A 56:974–978CrossRefPubMedGoogle Scholar
  27. 27.
    Paoli M, Anderson BF, Baker HM, Morgan WT, Smith A, Baker EN (1999) Crystal structure of hemopexin reveals a novel high-affinity heme site formed between two beta-propeller domains. Nat Struct Biol 6:926–931CrossRefPubMedGoogle Scholar
  28. 28.
    Fasano M, Fanali G, Leboffe L, Ascenzi P (2007) Heme binding to albuminoid proteins is the result of recent evolution. IUBMB Life 59:436–440CrossRefPubMedGoogle Scholar
  29. 29.
    Allhorn M, Berggard T, Nordberg J, Olsson ML, Akerstrom B (2002) Processing of the lipocalin alpha(1)-microglobulin by hemoglobin induces heme-binding and heme-degradation properties. Blood 99:1894–901CrossRefPubMedGoogle Scholar
  30. 30.
    Miller YI, Shaklai N (1999) Kinetics of hemin distribution in plasma reveals its role in lipoprotein oxidation. Biochim Biophys Acta 1454:153–164PubMedGoogle Scholar
  31. 31.
    Tolosano E, Fagoonee S, Morello N, Vinchi F, Fiorito V (2009) Heme Scavenging and the other facets of Hemopexin. Antioxid Redox SignalGoogle Scholar
  32. 32.
    Krishnamurthy P, Xie T, Schuetz JD (2007) The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther 114:345–358CrossRefPubMedGoogle Scholar
  33. 33.
    Latunde-Dada GO, Simpson RJ, McKie AT (2006) Recent advances in mammalian haem transport. Trends Biochem Sci 31:182–188CrossRefPubMedGoogle Scholar
  34. 34.
    Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P (1987) Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237:1210–1212CrossRefPubMedGoogle Scholar
  35. 35.
    McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371:508–510CrossRefPubMedGoogle Scholar
  36. 36.
    Sinha S, Mishra SK, Sharma S, Patibandla PK, Mallick PK, Sharma SK, Mohanty S, Pati SS, Ramteke BK, Bhatt R, Joshi H, Dash AP, Ahuja RC, Awasthi S, Venkatesh V, Habib S (2008) Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J 7:13CrossRefPubMedGoogle Scholar
  37. 37.
    Medzhitov R (2009) Damage control in host–pathogen interactions. Proc Natl Acad Sci U S A 106 15525–15526CrossRefPubMedGoogle Scholar
  38. 38.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756CrossRefPubMedGoogle Scholar
  39. 39.
    Clark IA (2007) How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev 18:335–343CrossRefPubMedGoogle Scholar
  40. 40.
    Tartaglia LA, Rothe M, Hu YF, Goeddel DV (1993) Tumor necrosis factor’s cytotoxic activity is signaled by the p55 TNF receptor. Cell 73:213–216CrossRefPubMedGoogle Scholar
  41. 41.
    Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331–367CrossRefPubMedGoogle Scholar
  42. 42.
    Beg AA, Baltimore D (1996) An essential role for NF-kB in preventing TNF-a-induced cell death. Science 274:782–784CrossRefPubMedGoogle Scholar
  43. 43.
    Churchill ME, Suzuki M (1989) ‘SPKK’ motifs prefer to bind to DNA at A/T-rich sites. Embo J 8:4189–4195PubMedGoogle Scholar
  44. 44.
    Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43CrossRefPubMedGoogle Scholar
  45. 45.
    Kumar S, Bandyopadhyay U (2005) Free heme toxicity and its detoxification systems in human. Toxicol Lett 157:175–188CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Instituto Gulbenkian de Ciência, Rua da Quinta GrandeOeirasPortugal
  2. 2.Instituto Gulbenkian de Ciência, Rua da Quinta GrandeOeirasPortugal

Personalised recommendations