Toll-like receptor 4 (TLR4) down-regulates microRNA-107 increasing macrophage adhesion via cyclin-dependent kinase 6

Abstract

Toll-like receptors (TLRs) modulate the expression of multiple microRNAs (miRNAs). Here we report the down-regulation of miR-107 by TLR4 in multiple cell types. The miR-107 sequence occurs in an intron within the sequence encoding the gene for Pantothenate kinase-1? (PanK1?), which is regulated by the transcription factor PPAR-?. PanK1? is also decreased in response to lipopolysaccharide (LPS). The effect on both miR-107 and PanK1? is consistent with a decrease in PPAR-? expression. We have found that the putative miR-107 target cyclin-dependent-kinase 6 (CDK6) expression is increased by TLR4 as a result of the decrease in miR-107. This effect is required for increased adhesion of macrophages in response to LPS, and CDK6- deficient mice are resistant to the lethal effect of LPS. We have therefore identified a mechanism for LPS signaling which involves a decrease in miR-107 leading to an increase in CDK6.