Neutrophil signaling pathways activated by bacterial DNA stimulation.
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-kappaB 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-kappaB. Moreover, we found that IL-8 production was markedly enhanced by inhibition of JNK, suggesting that this pathway negatively modulates NF-kappaB-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.
Alvarez
María E
ME
Departamento de Inmunología, Instituto de Investigaciones Hematológicas e Instituto de Estudios Oncológicos Fundación Maissa, Academia Nacional de Medicina, Buenos Aires, Argentina.
Fuxman Bass
Juan I
JI
Geffner
Jorge R
JR
Fernández Calotti
Paula X
PX
Costas
Mónica
M
Coso
Omar A
OA
Gamberale
Romina
R
Vermeulen
Mónica E
ME
Salamone
Gabriela
G
Martinez
Diego
D
Tanos
Tamara
T
Trevani
Analía S
AS
D000818:Animals; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000502:physiology*; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism / Q000382:microbiology*
D004269:DNA, Bacterial; D020928:Mitogen-Activated Protein Kinases