MicroRNAs modulate the noncanonical NF-κB pathway by regulating IKKα expression during macrophage differentiation

MicroRNAs are key regulators in many biological processes including cell differentiation. Here we show that during human monocyte-macrophage differentiation, the expression of the microRNAs miR-223, miR-15a, and miR-16 is dramatically decreased, leading to increased expression of the serine-threonine kinase IKKα in macrophages. In macrophages, higher IKKα expression in conjunction with stabilization of the kinase NIK induces elevated p52. Due to low RelB transcription factor expression in untreated macrophages, high p52 expression represses the basal level of both canonical and noncanonical NF-κB target genes. However, proinflammatory stimuli in macrophages result in greater induction of noncanonical NF-κB target genes. Thus a decrease in certain microRNAs likely prevents macrophage hyperaction yet primes the macrophage for certain responses to proinflammatory stimuli. NF-κB proteins are related transcription factors that bind to κB sites within the genome and regulate pro-inflammatory and immune-related genes1,2. They are therefore essential in the development, differentiation, and regulation of cells of the immune system. Two mammalian NF-κB proteins, p105 and p100, have long C-terminal domains that inhibit thei