IκB Kinase-Dependent Chronic Activation of NF-κB 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-κB participates in multiple cell functions, its role in cell differentiation is ill defined. Since differentiated macrophages, in contrast to cycling monocytes, contain significant levels of NF-κB in the nuclei, we questioned whether this transcription factor is involved in macrophage differentiation. Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of the promonocytic cell line U937 leads to persistent NF-κB nuclear translocation. We demonstrate here that an increased and persistent IKK activity correlates with monocyte differentiation leading to persistent NF-κB activation secondary to increased IκBα degradation via the IκB signal response domain (SRD). Promonocytic cells stably overexpressing an IκBα transgene containing SRD mutations fail to activate NF-κB and subsequently fail to survive the PMA-induced macrophage differentiation program. The differentiation-induced apoptosis was found to be dependent on tumor necrosis factor alpha. The protective effect of NF-κB is mediated through p21(WAF1/Cip1), since this protein was found to be regulated in an NF-κB-dependent manner and to confer survival features during macrophage differentiation. Therefore, NF-κB plays a key role in cell differentiation by conferring cell survival that in the case of macrophages is mediated through p21(WAF1/Cip1).