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      Plasmodium-infected erythrocytes (pRBC) induce endothelial cell apoptosis via a heme-mediated signaling pathway

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          Abstract

          Heme is cytotoxic to the plasmodium parasite, which converts it to an insoluble crystalline form called hemozoin (malaria pigment) in erythrocytes during replication. The increased serum levels of free heme cause tissue damage, activation of microvascular endothelial and glial cells, focal inflammation, activation of apoptotic pathways, and neuronal tissue damage. Several hypotheses have been proposed to explain how these causative factors exacerbate fatal malaria. However, none of them fully explain the detailed mechanisms leading to the high morbidity and mortality associated with malaria. We have previously reported that heme-induced brain microvascular endothelial cell (HBVEC) apoptosis is a major contributor to severe malaria pathogenesis. Here, we hypothesized that heme (at clinically relevant levels) induces inflammation and apoptosis in HBVEC, a process that is mediated by independent proinflammatory and proapoptotic signaling pathways. In this study, we determined the key signaling molecules associated with heme-mediated apoptosis in HBVEC in vitro using RT 2 profiler polymerase chain reaction array technology and confirmed results using immunostaining techniques. While several expressed genes in HBVEC were altered upon heme stimulation, we determined that the apoptotic effects of heme were mediated through p73 (tumor protein p73). The results provide an opportunity to target heme-mediated apoptosis therapeutically in malaria-infected individuals.

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          Most cited references 48

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          An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.

          Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA-/- fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-alpha. These results have implications for the treatment of inflammatory and proliferative diseases.
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            Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.

            A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14;18] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
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              Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.

              The t(14; 18) chromosomal translocation of human follicular B-cell lymphoma juxtaposes the bcl-2 gene with the immunoglobulin heavy chain locus. The bcl-2 immunoglobulin fusion gene is markedly deregulated resulting in inappropriately elevated levels of bcl-2 RNA and protein. Transgenic mice bearing a bcl-2 immunoglobulin minigene demonstrate a polyclonal expansion of resting yet responsive IgM-IgD B cells which display prolonged cell survival but no increase in cell cycling. Moreover, deregulated bcl-2 extends the survival of certain haematopoietic cell lines following growth-factor deprivation. By using immunolocalization studies we now demonstrate that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k). Overexpression of Bcl-2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                03 March 2016
                : 10
                : 1009-1018
                Affiliations
                Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA
                Author notes
                Correspondence: Mingli Liu; Jonathan K Stiles, Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA, Email mliu@ 123456msm.edu ; jstiles@ 123456msm.edu
                Article
                dddt-10-1009
                10.2147/DDDT.S96863
                4780719
                27042002
                © 2016 Liu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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