Group B Streptococcus induces TNF-alpha gene expression and activation of the transcription factors NF-kappa B and activator protein-1 in human cord blood monocytes
Jg. Vallejo et al., Group B Streptococcus induces TNF-alpha gene expression and activation of the transcription factors NF-kappa B and activator protein-1 in human cord blood monocytes, J IMMUNOL, 165(1), 2000, pp. 419-425
It has been postulated that production of TNF-alpha is central to the patho
genesis of septic shock induced by group B Streptococcus (GBS), In vitro st
udies using human cord blood monocytes have demonstrated that GBS induces T
NF-alpha secretion, but little is known about the intracellular signaling p
athways of TNF-alpha induction. In this report we show that heat-killed ser
otype IU GBS induces host cell signal transduction pathways that lead to ac
tivation of the transcription factors NF-kappa B and AP-1, Using adenoviral
transfer of I kappa B alpha (I kappa B alpha overexpression), the producti
on of TNF-alpha induced by whole GBS was inhibited by only 20%. We also sho
w that the p38 mitogen-activated protein kinase (MAPK) pathway is involved
in GBS-induced TNF-alpha secretion, because TNF-alpha protein and mRNA leve
ls in the presence of a specific inhibitor of p38 MAPK, SE 202190, were dra
matically diminished. EMSAs showed that SE 202190 inhibited GBS-induced AP-
1 activation, but had no effect on NF-kappa B-DNA binding activity. These r
esults indicate that both NF-kappa B and AP-1 (via p38 MAPK) are involved i
n the regulation of TNF-alpha production in GBS-stimulated neonatal monocyt
es, Therefore, disrupting the signal transduction pathways induced by GBS h
as the potential to attenuate the production of immune response mediators,
thereby halting or possibly reversing the course of this potentially fatal
disease.