Granulocyte apoptosis is a crucial part of the successful resolution of
inflammation. In vitro results show that activation of
NF-kappaB (
nuclear factor kappaB) in granulocytes is a survival mechanism.
NF-kappaB inhibitors increase the rate of constitutive apoptosis in neutrophils and eosinophils and cause these cells to respond to the pro-apoptotic effects of
TNF-alpha (tumour
necrosis factor-alpha). Results from both in vivo and in vitro experiments suggest that there are at least two important waves of
NF-kappaB activation in inflammatory loci, which increase the expression of COX-2 (cyclooxygenase-2), itself an
NF-kappaB controlled gene. The first wave causes the production of inflammatory mediators such as
PGE2 (
prostaglandin E2), allowing the establishment of
inflammation. The second wave causes the synthesis of
PGD2 and its metabolites that induce granulocyte apoptosis by inhibiting
NF-kappaB activation. These metabolites may therefore be important physiological mediators controlling the resolution of
inflammation. Although
NF-kappaB is an important target for anti-inflammatory
therapy, the timing of inhibition in vivo may be crucial, to ensure that production of
PGD2 and its sequential metabolites can occur.