Differential Regulation of Interleukin-1 Receptor-associated Kinase-1 (IRAK-1) and IRAK-2 by MicroRNA-146a and NF-κB in Stressed Human Astroglial Cells and in Alzheimer Disease*

Specific microRNAs (miRNAs), small non-coding RNAs that support homeostatic gene expression, are significantly altered in abundance in human neurological disorders. In monocytes, increased expression of an NF-κB-regulated miRNA-146a down-regulates expression of the interleukin-1 receptor-associated kinase-1 (IRAK-1), an essential component of Toll-like/IL-1 receptor signaling. Here we extend those observations to the hippocampus and neocortex of Alzheimer disease (AD) brain and to stressed human astroglial (HAG) cells in primary culture. In 66 control and AD samples we note a significant up-regulation of miRNA-146a coupled to down-regulation of IRAK-1 and a compensatory up-regulation of IRAK-2. Using miRNA-146a-, IRAK-1-, or IRAK-2 promoter-luciferase reporter constructs, we observe decreases in IRAK-1 and increases in miRNA-146a and IRAK-2 expression in interleukin-1β (IL-1β) and amyloid-β-42 (Aβ42) peptide-stressed HAG cells. NF-κB-mediated transcriptional control of human IRAK-2 was localized to between −119 and +12 bp of the immediate IRAK-2 promoter. The NF-κB inhibitors curcumin, pyrrolidine dithiocarbamate or CAY10512 abrogated both IRAK-2 and miRNA-146a expression, whereas IRAK-1 was up-regulated. Incubation of a protected antisense miRNA-146a was found to inhibit miRNA-146a and restore IRAK-1, whereas IRAK-2 remained unaffected. These data suggest a significantly independent regulation of IRAK-1 and IRAK-2 in AD and in IL-1β+Aβ42 peptide-stressed HAG cells and that an inducible, NF-κB-sensitive, miRNA-146a-mediated down-regulation of IRAK-1 coupled to an NF-κB-induced up-regulation of IRAK-2 expression drives an extensively sustained inflammatory response. The interactive signaling of NF-κB and miRNA-146a further illustrate interplay between inducible transcription factors and pro-inflammatory miRNAs that regulate brain IRAK expression. The combinatorial use of NF-κB inhibitors with miRNA-146a or antisense miRNA-146a may have potential as a bi-pronged therapeutic strategy directed against IRAK-2-driven pathogenic signaling.