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J. Biol. Chem., Vol. 282, Issue 33, 24430-24436, August 17, 2007

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Heme Induces Neutrophil Migration and Reactive Oxygen Species Generation through Signaling Pathways Characteristic of Chemotactic Receptors^*

Bárbara N. Porto¹, Letícia S. Alves, Patricia L. Fernández², Tatiana P. Dutra, Rodrigo T. Figueiredo², Aurélio V. Graça-Souza^¶, and Marcelo T. Bozza³

From the Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21.941-590 Brasil, the Institute of Advanced Scientific Investigations and High Technology Services, Ciudad de Panamá, 0816-02852 Panamá, and the ^¶Programa de Biotecnologia e Biologia Molecular, Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, 21.941-590 Brasil

Hemolysis or extensive cell damage can lead to high concentrations of free heme, causing oxidative stress and inflammation. Considering that heme induces neutrophil chemotaxis, we hypothesize that heme activates a G protein-coupled receptor. Here we show that similar to heme, several heme analogs were able to induce neutrophil migration in vitro and in vivo. Mesoporphyrins, molecules lacking the vinyl groups in their rings, were not chemotactic for neutrophils and selectively inhibited heme-induced migration. Moreover, migration of neutrophils induced by heme was abolished by pretreatment with pertussis toxin, an inhibitor of G inhibitory protein, and with inhibitors of phosphoinositide 3-kinase, phospholipase C, mitogen-activated protein kinases, or Rho kinase. The induction of reactive oxygen species by heme was dependent of G inhibitory protein and phosphoinositide 3-kinase and partially dependent of phospholipase C, protein kinase C, mitogen-activated protein kinases, and Rho kinase. Together, our results indicate that heme activates neutrophils through signaling pathways that are characteristic of chemoattractant molecules and suggest that mesoporphyrins might prove valuable in the treatment of the inflammatory consequences of hemorrhagic and hemolytic disorders.

Received for publication, April 30, 2007 , and in revised form, June 19, 2007.

^* This work was supported by Conselho de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação José Bonifácio (FuJB), and Programa de Núcleos de Excelência (Pronex) (to M. T. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a studentship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

² Supported by studentships from CNPq.

³ To whom correspondence should be addressed: Departamento de Imunologia, Instituto de Microbiologia, CCS Bloco I, UFRJ, Avenida Carlos Chagas Filho, 373 Cidade Universitária, Rio de Janeiro, RJ, 21941-902 Brasil. Tel.: 55-21-22700990; Fax: 55-21-25608344; E-mail: mbozza{at}micro.ufrj.br.

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