miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation
| Autor: | Susanne Richter, Thomas L. Bauer, Yvonne M. Schichl, Bernhard Gesslbauer, Herbert Strobl, Sabine Konradi, Jennifer Jurkin, Rene Koeffel |
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| Rok vydání: | 2010 |
| Předmět: |
Myeloid
medicine.medical_treatment Immunology Down-Regulation Biology Cell Line Cell therapy Transforming Growth Factor beta1 Proto-Oncogene Proteins medicine Immunology and Allergy Gene silencing Humans Myeloid Cells Transcription factor Cells Cultured U937 cell Monocyte Bacterial Infections Dendritic Cells U937 Cells Toll-Like Receptor 2 Cell biology TLR2 MicroRNAs medicine.anatomical_structure Cytokine Desensitization Immunologic Trans-Activators Epidermis |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 184(9) |
| ISSN: | 1550-6606 |
| Popis: | Langerhans cells (LCs) in epithelia and interstitial dendritic cells (intDCs) in adjacent connective tissues represent two closely related myeloid-derived DC subsets that exert specialized functions in the immune system and are of clinical relevance for cell therapy. Both subsets arise from monocyte-committed intermediates in response to tissue-associated microenvironmental signals; however, molecular mechanisms underlying myeloid DC subset specification and function remain poorly defined. Using microarray profiling, we identified microRNA (miRNA) miR-146a to be constitutively expressed at higher levels in human LCs compared with intDCs. Moreover, miR-146a levels were low in monocytes and nondetectable in neutrophil granulocytes. Interestingly, constitutive high miR-146a expression in LCs is induced by the transcription factor PU.1 in response to TGF-β1, a key microenvironmental signal for epidermal LC differentiation. We identified miR-146a as a regulator of monocyte and DC activation but not myeloid/DC subset differentiation. Ectopic miR-146a in monocytes and intDCs interfered with TLR2 downstream signaling and cytokine production, without affecting phenotypic DC maturation. Inversely, silencing of miR-146a in LCs enhanced TLR2-dependent NF-κB signaling. We therefore conclude that high constitutive miR-146a levels are induced by microenvironmental signals in the epidermis and might render LCs less susceptible to inappropriate activation by commensal bacterial TLR2 triggers at body surfaces. |
| Databáze: | OpenAIRE |
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