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 peroxisome proliferator-activating receptor ␣ (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.Toll-like receptors (TLRs) 2 are among the first line of defense in the body where they recognize conserved structures from bacteria, viruses, or fungi (1, 2). They play a critical role in innate immunity, and their activation leads to the transcription of genes involved in the immune and inflammatory responses. MicroRNAs (miRNAs) are an important family of small, noncoding RNAs that act as regulators of gene expression in a tissue-and cell-specific manner by base-pairing to a target messenger RNA (mRNA) sequence called a seed sequence. This leads to the partial or full degradation of the mRNA by RNases and the inhibition of its translation into a functional protein (3-5). miRNAs were originally found to have a role in cellular development, differentiation, adhesion, and apoptosis and are now known to function in cancer and immunity (5-8). Stimulation of cells with the TLR4-specific ligand LPS from Gramnegative bacteria results in an increase in the expression of several miRNAs including miR-21, miR-146a, and miR-155. miR-21 has been linked to cell migration, invasion, and adhesion, with target genes that include tropomyosin, programmed cell death protein 4 (PDCD4), and phosphatase and tensin homolog (PTEN). It was recently shown to regulate the immune response negatively by promoting the anti-inflammatory response by eliminating PDCD4 and up-regulating IL-10 (9, 10). miR-146a acts as a negative regulator of TLR signaling and cytokine production. Two genes known to be involved in TLR4 signaling, those encoding TRAF6 and IRAK1, are targets of miR-146a, and it was shown that LPS-induced activation of miR-146a is NF-B-dependent (11). miR-155 has been shown to target suppressor of cytokine signaling 1 (SOCS1) and SH2 (Src homology 2)-containing inositol phosphatase-1 (SHIP-1) directly. Mice lacking miR-155 have defects in B cell differentiation as well as having severe deficiencies in immune responses when exposed to pathogens (12-14). miRNAs have also been shown to be down-regulated in expression in response to LPS, including Let-7i and miR-125b, which have been show...

MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro

“…Interestingly, it has been reported that miR-129 overexpression leads to G1 cell cycle arrest and eventually to cell death (71). Since miR-107 has also been found to arrest the cell cycle in the G1 phase (19,25,37,57), we could speculate that this mechanism underlies our observations in GH3 and SH-SY5Y cells. However, further studies are necessary to confirm this hypothesis.…”

In vitro screening of LPS-induced miRNAs in leukocytes derived from cord blood and their possible roles in regulating TLR signals

“…For example, miR-181a was found to be concurrently upregulated with IL-1α, IL-1β, IL-6, and TNF-α in a mouse acute inflammatory state via a TLR4-dependent pathway (21). MiR-107, which was downregulated in response to LPS in multiple cell types (22), and let-7i, which was decreased in LPSstimulated cholangiocytes (23), were found to be affected in a MyD88-and NF-κB-dependent manner. Similar coexpression patterns between these miRNAs and TLR signaling compartments in our study might support those results.…”

CDK6 and miR-320c Co-Regulate Chondrocyte Catabolism Through NF-κB Signaling Pathways

“…miR-107 and miR-186 directly regulate CDK6 expression by interacting with the 3′-UTR of its mRNA to inhibit cancer cell proliferation [32,33]. Elizabeth et al demonstrated that Toll-like Receptor-4 (TLR4) down-regulated miR-107, thus increasing CDK6 expression and promoting macrophage adhesion [32]. However, it has been shown that individual or combined deletion of CDK4 and CDK6 does not affect the proliferation of normal cells [9,10].…”

“…CDKs perform various functions by regulating the cell cycle and gene expression, indicating their involvement in diverse biological processes [31]. miR-107 and miR-186 directly regulate CDK6 expression by interacting with the 3′-UTR of its mRNA to inhibit cancer cell proliferation [32,33]. Elizabeth et al demonstrated that Toll-like Receptor-4 (TLR4) down-regulated miR-107, thus increasing CDK6 expression and promoting macrophage adhesion [32].…”