Chloroquine inhibits human CD4+ T-cell activation by AP-1 signaling modulation
| Autor: | Katrin Goldhahn, Georg Greiner, Doris Trapin, Nadine Witzeneder, Peter Steinberger, Franz Ratzinger, Klaus G. Schmetterer, Guenter Steiner, Sabrina Jutz, Winfried F. Pickl, Gregor Hoermann, Marlene C. Gerner, Ralf Schmidt, Heinz Burgmann |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CD3 Complex MAP Kinase Kinase 4 Primary Cell Culture Lymphocyte Activation Article Antibodies Immunophenotyping 03 medical and health sciences CD28 Antigens medicine Humans Cell Lineage Viability assay Th1-Th2 Balance Interleukin 4 Multidisciplinary Interleukin-13 Dose-Response Relationship Drug Chemistry Chloroquine T helper cell T-Lymphocytes Helper-Inducer Acquired immune system 3. Good health Cell biology Transcription Factor AP-1 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Antirheumatic Agents Interleukin 13 Cytokine secretion Interleukin-4 Signal transduction Intracellular Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep42191 |
| Popis: | Chloroquine (CQ) is widely used as an anti-inflammatory therapeutic for rheumatic diseases. Although its modes of action on the innate immune system are well described, there is still insufficient knowledge about its direct effects on the adaptive immune system. Thus, we evaluated the influence of CQ on activation parameters of human CD4+ T-cells. CQ directly suppressed proliferation, metabolic activity and cytokine secretion of T-cells following anti-CD3/anti-CD28 activation. In contrast, CQ showed no effect on up-regulation of T-cell activation markers. CQ inhibited activation of all T helper cell subsets, although IL-4 and IL-13 secretion by Th2 cells were less influenced compared to other Th-specific cytokines. Up to 10 μM, CQ did not reduce cell viability, suggesting specific suppressive effects on T-cells. These properties of CQ were fully reversible in re-stimulation experiments. Analyses of intracellular signaling showed that CQ specifically inhibited autophagic flux and additionally activation of AP-1 by reducing phosphorylation of c-JUN. This effect was mediated by inhibition of JNK catalytic activity. In summary, we characterized selective and reversible immunomodulatory effects of CQ on human CD4+ T-cells. These findings provide new insights into the biological actions of JNK/AP-1 signaling in T-cells and may help to expand the therapeutic spectrum of CQ. |
| Databáze: | OpenAIRE |
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