Cell death and differentiation, 2008-12, Vol.15 (12), p.1901-1909
2008
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- Autor(en) / Beteiligte
- Titel
- TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells
- Ist Teil von
- Cell death and differentiation, 2008-12, Vol.15 (12), p.1901-1909
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2008
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor(s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E 2 (PGE 2 ) and showed that both APC-derived supernatants and PGE 2 prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE 2 receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE 2 . Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE 2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1350-9047eISSN: 1476-5403DOI: 10.1038/cdd.2008.128Titel-ID: cdi_proquest_miscellaneous_69790421
- Format
- –
- Schlagworte
- Animals, Antigens, Apoptosis, Autoimmune diseases, Biochemistry, Biomedical and Life Sciences, Bone marrow, CD3 Complex - metabolism, Cell Biology, Cell Cycle Analysis, Cell death, Cell Death - drug effects, Cyclic AMP-Dependent Protein Kinases - metabolism, Cytokines, Cytoprotection - drug effects, Dendritic cells, Dendritic Cells - cytology, Dendritic Cells - drug effects, Dendritic Cells - metabolism, Dinoprostone - biosynthesis, Fas Ligand Protein - genetics, Fas Ligand Protein - metabolism, Guanine Nucleotide Exchange Factors - metabolism, Immunology, Kinases, Life Sciences, Lipopolysaccharides - pharmacology, Lymphocytes, Macrophage Activation - drug effects, Macrophages - cytology, Macrophages - drug effects, Macrophages - metabolism, Mice, Myeloid Differentiation Factor 88 - metabolism, original-paper, Proteins, Receptors, Prostaglandin E - metabolism, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction - drug effects, Stem Cells, Subcellular Fractions - drug effects, Subcellular Fractions - metabolism, T-Lymphocytes - cytology, T-Lymphocytes - drug effects, T-Lymphocytes - metabolism, Toll-Like Receptor 4 - metabolism, Up-Regulation - drug effects