I kappa B kinase-dependent chronic activation of NF-kappa B is necessary for p21(WAF1/Cip1) inhibition of differentiation-induced apoptosis of monocytes

The molecular mechanisms regulating monocyte differentiation to macrophages remain unknown. Although the transcription factor NF-kappaB participates i n multiple tell functions, its role in cell differentiation is ill defined. Since differentiated macrophages, in contrast to cycling monocytes, contai n significant levels of NF-kappaB in the nuclei, me questioned whether this transcription factor is involved in macrophage differentiation. Phorbol 12 -myristate W-acetate (PMA)-induced differentiation of the promonocytic cell line U937 leads to persistent NF-kappaB nuclear translocation. We demonstr ate here that an increased and persistent IKK activity correlates with mono cyte differentiation leading to persistent NF-kappaB activation secondary t o increased I kappaB alpha degradation via the I kappaB signal response dom ain (SRD). Promonocytic cells stably overexpressing an I kappaB alpha trans gene containing SRD mutations fail to activate NF-kappaB and subsequently f ail to survive the PMA-induced macrophage differentiation program. The diff erentiation-induced apoptosis was found to be dependent on tumor necrosis f actor alpha. The protective effect of NF-kappaB is mediated through p21(WAF 1/Cip1), since this protein was found to be regulated in an NF-kappaB-depen dent manner and to confer survival features during macrophage differentiati on. Therefore, NF-kappaB plays a key role in cell differentiation by confer ring cell survival that in the case of macrophages is mediated through p21( WAF1/Cip1).