Abstract
Mammalian biological processes such as inflammation, involve regulation of hundreds of genes controlling onset and termination. MicroRNAs (miRNAs) can translationally repress target mRNAs and regulate innate immune responses. Our model system comprised primary human keratinocytes, which exhibited robust differences in inflammatory cytokine production (interleukin-6 and tumor necrosis factor-alpha) following specific Toll-like receptor 2 and 4 (TLR-2/TLR-4) agonist challenge. We challenged these primary cells with Porphyromonas gingivalis (a Gram-negative bacterium that triggers TLR-2 and TLR-4) and performed miRNA expression profiling. We identified miRNA (miR)-105 as a modulator of TLR-2 protein translation in human gingival keratinocytes. There was a strong inverse correlation between cells that had high cytokine responses following TLR-2 agonist challenge and miR-105 levels. Knock-in and knock-down of miR-105 confirmed this inverse relationship. In silico analysis predicted that miR-105 had complementarity for TLR-2 mRNA, and the luciferase reporter assay verified this. Further understanding of the role of miRNA in host responses may elucidate disease susceptibility and suggest new anti-inflammatory therapeutics.
Highlights
The innate immune response is a crucial first line of defense against pathogens
Host detection of microbes occurs through pattern recognition receptors, including Toll-like receptors (TLRs)2 that are expressed on many cells, including macrophages, monocytes [1], and keratinocytes [2]
MiR-105 Is Up-regulated in Human Gingival Keratinocytes with a Diminished Inflammatory Response—We hypothesized that miRNAs may play a role in innate immune response variation [25] and could differentiate periodontitis disease-susceptible and disease-resistant subjects
Summary
The innate immune response is a crucial first line of defense against pathogens. Host detection of microbes occurs through pattern recognition receptors, including Toll-like receptors (TLRs)2 that are expressed on many cells, including macrophages, monocytes [1], and keratinocytes [2]. There was a strong inverse correlation between cells that had high cytokine responses following TLR-2 agonist challenge and miR-105 levels. We identified innate immune variations within a bank of over 30 primary human gingival cell cultures [25] based on variations in cytokine response following TLR agonist challenge.
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