Chloroquine inhibits human CD4+T-cell activation by AP-1 signaling modulation.
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.
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Ralf L J
RL
Schmidt
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
Sabrina
S
Jutz
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria.|Cluster Arthritis and Rehabilitation, Department of Degenerative Joint Diseases, Ludwig Boltzmann Society, Vienna, Austria.
Katrin
K
Goldhahn
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Nadine
N
Witzeneder
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Marlene C
MC
Gerner
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
Doris
D
Trapin
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Georg
G
Greiner
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Gregor
G
Hoermann
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria.|Cluster Arthritis and Rehabilitation, Department of Degenerative Joint Diseases, Ludwig Boltzmann Society, Vienna, Austria.
Guenter
G
Steiner
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
Winfried F
WF
Pickl
Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
Heinz
H
Burgmann
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
Peter
P
Steinberger
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Franz
F
Ratzinger
Department of Laboratory Medicine, Medical University of Vienna, Austria.
Klaus G
KG
Schmetterer
D000906:Antibodies / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000187:drug effects* / Q000276:immunology; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D018501:Antirheumatic Agents; D018106:CD28 Antigens; D017252:CD3 Complex; C578095:IL13 protein, human; C508598:IL4 protein, human; D018793:Interleukin-13; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D002738:Chloroquine; D048670:MAP Kinase Kinase 4