Selective use of TRAM in lipopolysaccharide (LPS) and lipoteichoic acid (LTA) induced NF-kappaB activation and cytokine production in primary human cells: TRAM is an adaptor for LPS and LTA signaling
| Autor: | Marc Feldmann, Sandra Sacre, Evangelos Andreakos, Corinne Taylor, Brian M. J. Foxwell, Anna M. Lundberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
Lipopolysaccharide medicine.medical_treatment Immunology Umbilical Cord Mice chemistry.chemical_compound Species Specificity Animals Humans Immunology and Allergy Medicine Cells Cultured Adaptor Proteins Signal Transducing Mice Knockout business.industry Macrophages Synovial Membrane NF-kappa B Endothelial Cells Lipopeptide Signal transducing adaptor protein Receptors Interleukin Fibroblasts Embryo Mammalian Toll-Like Receptor 2 Cell biology Teichoic Acids Toll-Like Receptor 4 Adaptor Proteins Vesicular Transport TLR2 Toll-Like Receptor 6 Cytokine chemistry Organ Specificity Cell culture TLR4 Lipoteichoic acid business Signal Transduction |
| DOI: | 10.4049/jimmunol.178.4.2148 |
| Popis: | TLR signal via Toll-IL-1R (TIR) homology domain-containing adaptor proteins. One of these adaptors, Toll-IL-1R domain-containing adaptor inducing IFN-β-related adaptor molecule (TRAM), has been shown to be essential for TLR4 signaling in TRAM−/− mice and cell lines. Previously, we showed that MyD88 or Mal dominant-negative constructs did not inhibit LPS induction of cytokines in primary human M-CSF-derived macrophages. A possible explanation was redundancy of the adaptors during LPS signaling. TRAM is a suitable candidate to compensate for these adaptors. To investigate a potential role for TRAM in LPS signaling in human M-CSF-derived macrophages, we engineered an adenoviral construct expressing dominant-negative TRAM-C117H (AdTRAMdn). Synovial fibroblasts (SF) and human umbilical endothelial cells (HUVECs) were used as a nonmyeloid comparison. AdTRAMdn inhibited LPS-induced signaling in SFs and HUVECs, reducing NF-κB activation and cytokine production, but did not inhibit LPS signaling in M-CSF-derived human macrophages. Further investigation of other TLR ligands showed that AdTRAMdn was also able to inhibit signaling initiated by lipoteichoic acid, a TLR2 ligand, in SFs and HUVECs and lipoteichoic acid and macrophage-activating lipopeptide 2 signaling was also inhibited in TRAM−/− murine embryonic fibroblasts. We conclude that TRAM is an adaptor protein for both TLR4 and TLR2/6 signaling in SFs, HUVECs, and murine embryonic fibroblasts, but cannot demonstrate a role in human macrophages. |
| Databáze: | OpenAIRE |
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