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Neutrophil Signaling Pathways Activated by Bacterial DNA Stimulation¹

María E. Alvarez^*,, Juan I. Fuxman Bass^*,, Jorge R. Geffner^*,, Paula X. Fernández Calotti^*,, Mónica Costas, Omar A. Coso, Romina Gamberale^*,, Mónica E. Vermeulen^*,, Gabriela Salamone^*,, Diego Martinez^*,, Tamara Tanos and Analía S. Trevani^2,*,

^* Departamento de Inmunología, Instituto de Investigaciones Hematológicas e Instituto de Estudios Oncológicos "Fundación Maissa," Academia Nacional de Medicina, Buenos Aires, Argentina; Departamento de Microbiología, Facultad de Medicina, and Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; and Instituto de Investigaciones Médicas "Alfredo Lanari," Buenos Aires, Argentina

We have previously shown that bacterial DNA activates human neutrophils in a CpG-independent manner. In this study, we have characterized the signaling pathways involved in the activation mechanism. We found that p38 MAPK, ERK1/2, and JNK pathways, as well as the PI3K/Akt pathway, are activated by bacterial DNA. We also determined that bacterial DNA induces NF-B and AP-1 activation. When analyzing the role of these pathways on neutrophil functions, we observed that up-regulation of CD11b triggered by bacterial DNA was decreased by pharmacological inhibitors of the p38 MAPK, ERK1/2, and JNK, whereas stimulation of IL-8 release was dependent on p38, ERK1/2, and NF-B. Moreover, we found that IL-8 production was markedly enhanced by inhibition of JNK, suggesting that this pathway negatively modulates NF-B-dependent transcription. We also observed that bacterial DNA stimulated IL-1R-associated kinase-1 kinase activity and its partial degradation. Finally, we determined that bacterial DNA stimulated CD11b up-regulation in TLR9^–/– but not in MyD88^–/– mouse neutrophils, supporting that bacterial DNA induces neutrophil activation through a TLR9-independent and MyD88-dependent pathway.

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 This work was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Agencia Nacional de Promoción Científica y Tecnológica, Universidad de Buenos Aires, and Fundación Alberto Roemmers (Argentina).

² Address correspondence and reprint requests to Dr. Analía S. Trevani, Instituto de Investigaciones Hematológicas–Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. E-mail address: atrevani{at}medscape.com

³ Abbreviations used in this paper: BMC, bone marrow chimeric; MEKK, mitogen-activated protein kinase kinase; IRAK, IL-1R-associated kinase; Pam3CSK4, Pam3-Cys-Ser-Lys4; TRAF6, TNFR-associated factor 6; ALLN, N-acetyl-leucinyl-leucinyl-norleucinal; AEBSF, 4-(2-aminoethyl) benzenesulfonylfluoride; ODN, oligonucleotide; MBP, myelin basic protein; TIR, Toll-IL-1R.

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