Enhanced NF-κB activation and cellular function in macrophages lacking IκB kinase 1 (IKK1)

IκB kinase (IKK) complex plays a key regulatory role in macrophages for NF-κB activation during both innate and adaptive immune responses. Because IKK1–/– mice died at birth, we differentiated functional macrophages from embryonic day 15.5 IKK1 mutant embryonic liver. The embryonic liver-derived macrophage (ELDM) showed enhanced phagocytotic clearance of bacteria, more efficient antigen-presenting capacity, elevated secretion of several key proinflammatory cytokines and chemokines, and known NFκB target genes. Increased NFκB activity in IKK1 mutant ELDM was the result of prolonged degradation of IκBα in response to infectious pathogens. The delayed restoration of IκBα in pathogen-activated IKK1–/– ELDM was a direct consequence of uncontrolled IKK2 kinase activity. We hypothesize that IKK1 plays a checkpoint role in the proper control of IκBα kinase activity in innate and adaptive immunity.