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* 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.
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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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