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dc.contributor.author
Fortes, Guilherme B.
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Alves, Leticia S.
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Olivera, Rosane de
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Dutra, Fabianno F.
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Rodrigues, Danielle
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Fernandez, Patricia F.
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Souto Padron, Thais
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de Rosa, Maria Jose
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Kelliher, Michelle
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Golenbock, Douglas
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Chan, Francis K. M.
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Bozza, Marcelo T.
dc.date.available
2018-04-12T20:06:47Z
dc.date.issued
2012-01
dc.identifier.citation
Fortes, Guilherme B.; Alves, Leticia S.; Olivera, Rosane de; Dutra, Fabianno F.; Rodrigues, Danielle; et al.; Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production.; American Society of Hematology; Blood; 119; 10; 1-2012; 2368-2375
dc.identifier.issn
0006-4971
dc.identifier.uri
http://hdl.handle.net/11336/41909
dc.description.abstract
Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society of Hematology
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Macrophages
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
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dc.title
Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production.
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-04-12T14:24:28Z
dc.journal.volume
119
dc.journal.number
10
dc.journal.pagination
2368-2375
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington, DC
dc.description.fil
Fil: Fortes, Guilherme B.. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Alves, Leticia S.. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Olivera, Rosane de. University of Massachussets; Estados Unidos. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Dutra, Fabianno F.. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Rodrigues, Danielle. Universidade Federal do Rio de Janeiro; Brasil
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Fil: Fernandez, Patricia F.. Instituto de Investigaciones Científicas y Servicios de Alta Tecnología; Panamá
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Fil: Souto Padron, Thais. Instituto de Investigaciones Cientificas y Servicios de alta Tecnología; Panamá
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Fil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
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Fil: Kelliher, Michelle. University of Massachussets; Estados Unidos
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Fil: Golenbock, Douglas. University of Massachussets; Estados Unidos
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Fil: Chan, Francis K. M.. University of Massachussets; Estados Unidos
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Fil: Bozza, Marcelo T.. Universidade Federal do Rio de Janeiro; Brasil
dc.journal.title
Blood
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358230/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1182/blood-2011-08-375303
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info:eu-repo/semantics/altIdentifier/url/http://www.bloodjournal.org/content/119/10/2368
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