Heme Sensitization to TNF-Mediated Programmed Cell Death
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.
KeywordsTumor Necrosis Factor Programme Cell Death Severe Malaria Cerebral Malaria Blood Stage
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.
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