A. Hida et al., Nuclear factor-kappa B and caspases co-operatively regulate the activationand apoptosis of human macrophages, IMMUNOLOGY, 99(4), 2000, pp. 553-560
Accumulating evidence suggests that macrophages function as major effector
cells in the pathological process of various human diseases. We examined he
re the role of nuclear factor-kappa B (NF-kappa B) and caspases in the regu
lation of activation and apoptosis of macrophages. Activation of the human
monoblastic leukaemia cell line, U937, by phorbol 12-myristate 13-acetate (
PMA) increased the expression of CD14/CD86, and cytokine production. PMA st
imulation also increased the expression of both pro-caspase-8 and pro-caspa
se-3 in U937, but not apoptosis or intracellular caspase-3 activity. PMA al
so increased the expression of X-chromosome-linked inhibitor of apoptosis p
rotein (XIAP) in U937, suggesting an inhibitory action for XIAP on the casp
ase cascade in PMA-stimulated U937. Electrophoretic mobility shift assay (E
MSA) showed a significant increase of nuclear NF-kappa B activity in PMA-st
imulated U937. When a potent NF-kappa B inhibitor, pyrrolidine dithiocarbam
ate (PDTC), was added to U937 cell culture in the presence of PMA, apoptosi
s was triggered by activation of caspase-3, which was induced by caspase-8
activation. XIAP expression was markedly suppressed in PMA-treated U937 in
the presence of PDTC. The inhibitors of caspase-8 and caspase-3 mostly inhi
bited apoptosis of U937 treated with PMA in the presence of PDTC. Furthermo
re, a phenotype of U937 treated with PMA and PDTC in the presence of caspas
e inhibitor was almost identical to that of unstimulated U937. Our results
suggest that the signalling pathways involved in the activation and apoptos
is of human macrophages could be co-operatively regulated by the use of NF-
kappa B and caspase inhibitors, thus enabling the control of macrophage fun
ction and number.