Neutrophil signaling pathways activated by bacterial DNA stimulation.

ALVAREZ ME, BASS JI, GEFFNER JR, CALOTTI PX, COSTAS M, COSO OA, GAMBERALE R, VERMEULEN E.M., SALAMONE G., MARTÍNEZ D., TANOS T., TREVANI A.S

JOURNAL OF IMMUNOLOGY

The American Association of Immunologists

Lugar: New York; Año: 2006 vol. 177 p. 4037 - 4046

0022-1767

We have previously shown that bacterial DNA activates human neutrophils in aCpG-independent manner. In this study, we have characterized the signalingpathways 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 bacterialDNA. We also determined that bacterial DNA induces NF-kappaB and AP-1activation. When analyzing the role of these pathways on neutrophil functions,we observed that up-regulation of CD11b triggered by bacterial DNA was decreasedby pharmacological inhibitors of the p38 MAPK, ERK1/2, and JNK, whereasstimulation 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 ofJNK, suggesting that this pathway negatively modulates NF-kappaB-dependenttranscription. We also observed that bacterial DNA stimulated IL-1R-associatedkinase-1 kinase activity and its partial degradation. Finally, we determinedthat bacterial DNA stimulated CD11b up-regulation in TLR9(-/-) but not inMyD88(-/-) mouse neutrophils, supporting that bacterial DNA induces neutrophilactivation through a TLR9-independent and MyD88-dependent pathway.